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Review

Liver Sinusoidal Endothelium: The Hidden Interface in the Gut–Liver Axis in Metabolic Dysfunction-Associated Steatotic Liver Disease?

by
Ting Chen
1,
Aldo Grefhorst
1,* and
Adriaan G. Holleboom
1,2
1
Department of Experimental Vascular Medicine, Amsterdam University Medical Centers, 1105 AZ Amsterdam, The Netherlands
2
Department of Vascular Medicine, Amsterdam University Medical Centers, 1105 AZ Amsterdam, The Netherlands
*
Author to whom correspondence should be addressed.
Lipidology 2025, 2(2), 10; https://doi.org/10.3390/lipidology2020010
Submission received: 23 April 2025 / Revised: 26 May 2025 / Accepted: 27 May 2025 / Published: 29 May 2025
Browse Figure
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Abstract

:
Background/Objectives: Recent studies show that the gut microbiome plays a pivotal role in the (patho)physiology of metabolic dysfunction-associated steatotic liver disease (MASLD), likely via metabolites they produce that are transported via the portal vein towards the liver where they first encounter liver sinusoidal endothelial cells (LSECs). LSECs may modulate the effects the gut microbes have on the liver, e.g., on the progression of MASLD. Methods: This review aims to describe the current knowledge on the role of LSECs in mediating the effect of gut microbial products in MASLD. Results: Various studies show that LSECS have a contributing role in MASLD pathogenesis, suggesting that proper LSEC functionality is required to protect the liver from gut-driven attacks. Conclusions: Dedicated studies on the role and effects of gut-derived molecules on LSEC functionality are lacking, likely because such studies depend on labor-intensive techniques such as scanning electron microscopy (SEM).
Keywords:
LSEC; MASLD; gut microbes

1. The Gut–Liver Axis in MASLD

Metabolic dysfunction-associated steatotic liver disease (MASLD), previously termed non-alcoholic fatty liver disease (NAFLD), is defined as hepatic steatosis accompanied by at least one metabolic dysfunction, i.e., elevated body mass index (BMI), increased waist circumference, hyperglycemia, hypertension, or hyperlipidemia, in the absence of excessive alcohol consumption, drug use, or other specific causes. The spectrum of MASLD ranges from simple steatosis via metabolic dysfunction-associated steatohepatitis (MASH) to finally fibrosis and even cirrhosis [1]. The current global prevalence of MASLD is more than 30% [2]. The dramatic increase in MASLD-associated cirrhosis over the past decade emphasizes the need for prevention and treatment of MASLD [3]. Unfortunately, apart from lifestyle changes, there is currently limited treatment for MASLD. Recently, the first pharmacological MASH treatment, resmetirom, was approved by the FDA [4]. Resmetirom is a partial activator of the thyroid hormone receptor via which it suppresses hepatic lipid accumulation [5].
Recent studies show a role for the gut microbiome in the (patho)physiology of MASLD [6,7,8,9,10], likely via metabolites they produce. These metabolites are transported via the portal vein towards the liver, where they first encounter liver sinusoidal endothelial cells (LSECs). LSECs may modulate the effects gut microbes have on the liver, for instance, on the progression of MASLD. This review aims to describe the current knowledge on the role of the LSECs in mediating the effect of gut microbial products in MASLD. For this, we will first discuss LSEC physiology and its disturbance in MASLD before describing the interplay between gut metabolites, LSECs, and MASLD.

2. LSEC Physiology

The liver harbors a heterogeneous cell population: hepatocytes and non-parenchymal cells, such as LSECs, Kupffer cells (KCs), and hepatic stellate cells (HSCs). While the roles of the hepatocytes, HSCs, and KCs, as well as their interplay, have been extensively studied in MASLD, as recently reviewed [11], the attribution of LSECs to the initiation and progression of MASLD is relatively understudied. This is rather remarkable since LSECs constitute the largest proportion of non-parenchymal cells making up approximately 10% of liver mass [12], are the first contact between the circulating blood and hepatocytes [13], and several animal studies report that LSEC dysfunctionality occurs in the initial stage of MASLD [14,15,16].
LSECs are a highly specialized type of endothelial cells lining the sinusoidal spaces within the liver, which are filled with a mixture of arterial and portal vein blood. LSECs lack a basement membrane and have fenestrae [17], features that allow a rapid bidirectional substance exchange from the circulation to the hepatocyte over the endothelium. Numerous scavenger receptors make LSECs potent scavenger cells [18,19]. In addition, LSECs contribute to the abundance of (patho)physiological processes, including hemostasis, vascular tone, metabolite transport [20], thrombosis, inflammation, and angiogenesis [21,22].

2.1. Fenestrae

LSECs are highly permeable due to the fenestrae, the absence of a diaphragm, and the lack of a basement membrane [13]. Fenestrae are small pores with a 50–300 nm diameter that allow a bidirectional exchange of molecules such as nutrients, lipoproteins, viruses, and drugs from the blood compartment to the space of Disse [23,24,25]. Fenestrae are distributed either evenly or clustered into groups of tens to hundreds in so-called sieve plates [26]. The diameter and number of the fenestrae in a sieve plate might vary according to their location: larger but fewer fenestrae per plate are found in the periportal region, while the perivenous region contains smaller but more fenestrae per plate [26]. This difference is thought to be related to gradient blood changes between those two zones, e.g., higher local oxygen content [27], more nutrients [28], and higher concentration of gut-derived metabolites [29] in the periportal region. As a highly dynamic cellular feature, fenestrae can be manipulated by various factors [30]. For instance, defenestration (or capillarization), characterized as loss of fenestration, occurs during aging [31,32], likely due to dyslipidemia [33]. Defenestration has also been reported to occur due to fatty acids [32], oxidized low-density lipoprotein (ox-LDL) [32], alcohol [34], and the gut bacterial composition [35]. It is not known whether and how defenestration can be reversed in vivo despite some efforts from in vitro studies. Vascular endothelial growth factor (VEGF) produced by hepatocytes and HSCs [36,37] was reported among the factors that increase LSECs porosity and maintain fenestrae in vitro [38,39,40], likely via induction of nitric oxide (NO) production in LSECs [41,42]. Moreover, a recent study found that fenestrae can also be maintained in vitro by bone morphogenetic protein 9 (BMP9) [36], which is mainly secreted by HSCs. However, in general, there is a lack of knowledge of the mechanisms underlying LSEC defenestration in MASLD.

2.2. Nitric Oxide in LSEC Functionality

Relatively low but consistent NO produced by eNOS in the LSECs is essential to maintain the proper sinusoidal blood flow [37], which is generally activated by increased shear stress [37]. Moreover, NO produced by LSECs is important in whole liver physiology since it keeps HSCs quiescent [43] and contributes to the regeneration of hepatocytes after liver injury [44], thus maintaining normal liver homeostasis. The expression of eNOS is higher in periportal LSECs than in pericentral localized LSECs [45], which might be related to the distinct fenestrae pattern, and a single-cell transcriptomic study showed that pericentral localized LSECs are most susceptible to injury. With respect to MASLD, research on LSEC resistance and NO synthesis during MASLD progression is lacking, especially with respect to the early stages of MASLD. It is known that in cirrhotic liver, particularly in the pericentral zone, several genes representing capillarization are upregulated, while the expression of genes encoding endocytic receptors and factors involved in NO signaling is reduced [46]. The variations in NO produced in the different zones might be correlated with the variations in the LSEC resistance to increased shear stress [37], albeit that Su et al. found the gene expression related to vascular resistance was similar in normal control and carbon tetrachloride (CCl4)-induced cirrhotic mice [46].

2.3. LSECs: A Potent Scavenger System

LSECs are among the most powerful scavenger cells due to the large amount of scavenger receptors (SRs) [47] that are responsible for substrate turnover and waste clearance [48]. See Table 1, which depicts an overview of SRs found on LSECs [49].
Turnover of certain metabolic products is necessary to maintain normal liver functionality. For example, hyaluronic acid, an important biomarker for fibrosis, can be cleared by SR-K1 (CD44) [50]. In addition, collagen fragments can be eliminated by SR-E3 (MRC1/CD206) [51,52]. The cooperation of MRC1 and CD44, as well as other SRs, ensures normal turnover of extracellular matrix (ECM), protecting the liver from fibrosis. In addition, MRC1 is a rather LSEC-specific protein since it is not expressed on other endothelial cells in, for instance, the heart, lungs, or skeletal muscles [53]. Since MRC1 facilitates the recruitment of lysosomal enzymes [54], this at least partially explains the high activity of lysosomal enzymes and powerful clearance ability of LSECs [55].
Sinusoidal blood is a mixture of blood from the portal vein and the hepatic artery, and thus enriched with nutrients and gut-derived metabolites. LSECs constitute the first line of control of the liver for these nutrients and metabolites and can modulate their influx as well as the role these nutrients and metabolites might play in liver homeostasis. The burden of the influx of excessive lipids, e.g., adipose tissue-derived free fatty acids (FFAs) and lipoproteins such as chylomicron remnants, is a significant driving factor of MASLD. As the first line of defense in the liver, LSECs possess a powerful lipid clearance ability through various SRs.
SR-A (MSR1) can clear a wide range of ligands, including modified atherogenic lipoproteins such as oxidized low-density lipoproteins (LDL) and acetylated LDL particles (ac-LDL) [56]. These modified LDL particles can also be removed by SR-B1 (SCARB1) [57,58], a scavenger receptor that clears high-density lipoprotein (HDL) derived cholesteryl esters as well [59].
SR-B2, or CD36, is a transporter of, amongst others, FFAs that is highly expressed in LSECs compared to other endothelial cells [60]. Cd36 knockout mice have elevated fasting plasma FFA concentrations [61] but also an impaired hepatic HDL uptake [62], suggesting that CD36 has a role in HDL clearance. The importance of endothelial CD36 has been shown in a study with endothelial cell-specific Cd36 knockout mice that had a strongly reduced uptake of FFAs in the heart, whereas CD36-deficiency in cardiomyocytes did not influence FFA uptake by the heart [63]. Whether and how CD36 in LSECs controls the hepatic FFA uptake is not known.
SR-H1/Stabilin-1, as well as SR-H2/Stabilin-2, are known to be highly expressed in LSECs, where they are in charge of oxLDL clearance [64]. Low-density lipoprotein receptor-related protein-1 (LRP-1/SR-L1) is a multifunctional receptor that clears circulating Apolipoprotein E (ApoE) containing particles such as chylomicron remnants and very low-density lipoprotein (VLDL) [65]. A lack of LRP-1 leads to more severe high-fat diet (HFD)-induced hepatic insulin resistance and liver steatosis in mice [66].
In addition to excessive circulating lipids, there are numerous metabolic waste molecules that are cleared by SRs on LSECs. For instance, advanced glycation end products (AGEs), a biomarker for risk of MASLD severity [67] that aggravate MASLD via modulation of hepatic inflammation and fibrosis [68], can be eliminated by SR-A [56], STAB1/2 [69,70], and SR-J (a receptor for advanced glycation end-products, RAGE) [71] on LSECs. Notably, one of the most important roles of LSECs is to form a barrier to protect liver parenchymal cells from gut-derived toxins such as lipopolysaccharides (LPS). LPS is the main component of the outer cell wall of Gram-negative bacteria that aggravates hepatic inflammation [72]. The clearance of LPS is mainly performed by STAB1/2 on LSECs [73,74]. The interaction between CD44 and hyaluronan (HA) seems to be necessary for LPS-induced neutrophil recruitment in inflamed LSECs [75].

2.4. LSECs as Gatekeepers Against Microbes and Products from the Gut Lumen

In the last two decades, the connection between the gut microbiome and the metabolic syndrome has gathered more scientific as well as public attention. The idea of a gut-liver axis was postulated in the early 2000s and describes the bidirectional crosstalk between the intestine and the liver [76,77]. In this concept, gut microbes affect the liver by having a higher permeability of bacteria and their products due to an impaired intestinal barrier, through the portal vein [78]. As described above, LSECs constitute the first hepatic barrier against portal blood encounters upon enrichment with gut microbial-derived products. It is therefore likely that LSECs are affected by these products and hence modulate MASLD. The remainder of this review will focus on the evidence concerning LSEC functionality in MASLD and the gut–liver axis.

3. LSECs: Pathological Morphology and Function in MASLD

3.1. LSEC Functionality and Capillarization in MASLD

The research on the role of LSECs in the gut–liver axis in MASLD is hampered by the lack of ideal cell lines. Even primary LSECs quickly lose their typical LSEC phenotype, such as the fenestrate, when kept in culture [30]. Since there is no proven marker of LSEC functionality, e.g., protein or mRNA expression as a proxy of the degree of fenestration, scanning electron microscopy (SEM) for fenestrae is still the gold standard to assess fenestration. However, it is time-consuming and requires dedicated and skilled personnel. LSEC capillarization, as mentioned before, represents a loss of typical features of LSECs and thus potentially indicates cellular dysfunction.
Several studies report that LSEC capillarization occurs in the initial stage of MASLD [79]. Miyao et al., for instance, found that already 1 week of feeding mice a choline-deficient L-amino acid-defined (CDAA) diet resulted in an approximately 20% decrease in the fenestrae area [16]. Consistently, the fenestrae area was continuously reduced over the time of the CDAA diet [14]. CDAA is a rather harsh method to induce MASLD; feeding mice HFD better reflects the human situation. Peng et al. found that LSEC capillarization started after at least a 6-week HFD [16]. It might be even earlier than 6 weeks, but the researchers did not perform SEM before this time point. It is thought that the early changes in LSEC physiology may be mediated by certain macronutrients. One study showed that porosity and frequency of fenestrae were negatively associated with dietary fat intake, while the diameters of fenestrae were inversely associated with protein and carbohydrate intake [35]. FFAs have also been implicated in controlling LSEC fenestration. This is of clinical relevance since in most clinical cases the main source of hepatic fat is thought to be from circulating adipose tissue-derived FFAs resulting from reduced insulin sensitivity [80,81] of the lipolytic pathway in adipocytes [82]. It explains why overweight/obesity is one of the main drivers of MASLD, especially abdominal obesity caused by visceral fat accumulation [83]. A recent study reported that incubation of primary human LSECs with saturated fatty acids such as palmitate increased the expression of Semaphorin-3A, a protein thought to reduce porosity of LSECs [31]. Of note, different types of FFAs may have opposite effects on fenestrae. For instance, Hang et al. observed that 50 μM oleic acid maintained the phenotype of isolated rat-LSECs, including fenestrae [84]. In an in vitro study, incubation with ox-LDL decreased the size and number of fenestrae in primary human LSECs [79].
Not only do factors that result in MASLD affect LSEC functionality, but LSECs also interfere with MASLD development. LSEC capillarization is always related to an altered function of LSECs, including reduced NO production [85,86], hampered filtration capacity [87], and enhancement of liver fibrosis [88,89] and inflammation [90], and thus, in general, an aggravation of MASLD progression.
An impaired lipid turnover by defenestrated LSECs may serve as the first driver for MASLD. A recent study showed that deletion of plasmalemma vesicle-associated protein (PLVAP), which is crucial in LSEC fenestration [91], not only decreased the number of fenestrae but also resulted in higher plasma chylomicron and LDL concentrations in conjunction with more severe hepatic steatosis [92]. Among the explanations for this intrinsic relationship are the fact that the normal influx of LDL- and HDL-cholesterol from the sinusoid to the hepatocyte is blocked by capillarized LSECs, which will result in the loss of inhibition of de novo lipogenesis [79] and thus an increased hepatic lipid content. In addition, capillarized LSECs might inhibit the secretion of VLDL from hepatocytes in circulation, a feature that likely also results in an enhanced lipid accumulation in the hepatocytes [31,79,92].
Capillarization of LSECs also results in a loss of ability of the LSECs to keep HSCs quiescent and therefore alters the phenotype of KCs, contributing to ECM production and liver inflammation and thus promoting MASLD progression. It is currently unknown how these latter effects are mediated, but altogether, the rescue of capillarized LSECs may be a new therapeutic goal to treat or prevent MASLD.

3.2. LSEC Scavenger Receptors in MASLD

While capillarization is studied in MASLD, albeit still marginally, changes in LSEC SRs have not been addressed in MASLD. Table 2 shows the known changes in SRs in MASLD, which are in the majority of the whole liver rather than (isolated) LSECs. Hence, further investigations are needed to uncover the role of SRs in LSECs in MASLD, e.g., by performing dedicated studies with an analysis on primary LSECs isolated from various rodent as well as human MASLD livers.

3.3. Impaired NO Production and Reduced NO Sensitivity in MASLD

In the initial stage of MASLD, a temporary increased eNOS-mediated NO production in LSEC was observed, possibly due to an increased VEGF and transforming growth factor β-1 (TGF-β1) secretion by hepatocytes and HSCs in response to excessive lipid [93]. However, with the progression towards MASH, the eNOS/NO signaling is inhibited [94]. In addition, Ekumi et al. found that this reduced NOS by itself also significantly increased the liver triglyceride and cholesterol content by promoting triglyceride synthesis and cholesterol uptake in a rat model of hypertension [95]. In line, eNOS-deficient mice fed HFD have more fat in their liver [96] and an increased hepatocellular inflammation and fibrosis [97,98] than their wild-type littermates. In contrast, statins have been shown to improve MASLD by recovering the eNOS expression and NO production [99].
Apart from the effect on lipid metabolism, the reduced NO produced by LSECs in MASLD also contributes to the progression towards MASH via an effect on the inflammatory status. For instance, the reduced NO will result in activation of notch/NF-κB signaling [85] and induction of the proinflammatory transformation of macrophages [100,101,102], which is characterized by an enhanced production of ROS and inflammatory cytokines, finally contributing to hepatic inflammation and insulin resistance [103,104]. Moreover, less NO, combined with LSEC-derived extracellular vesicles, may attenuate the fibrogenic phenotype of activated HSCs [105]. HSCs, when activated, are primarily responsible for liver fibrosis [106] and can respond to and regulate inflammation in MASLD [107]. Though multiple pathways can trigger fibrosis, the activation of HSCs is a highly conserved process, which takes dominant responsibility for ECM accumulation and abnormal repairment [108].

4. Novel Perspectives on LSECs in MASLD: Hyperlipidemia, Hyperglycemia, Insulin Resistance, and Hypertension

The novel identifying criteria of MASLD emphasize the close relationship between steatotic disease and other metabolic disorders. Previous studies revealed the involvement of LSECs in those types of disorders. As described above, the increased burden from hyperlipidemia can be a challenge to LSECs, being a trigger in MASLD development and progression. Vice versa, an impaired LSEC barrier may block lipoprotein exchange between circulation and the liver and, hence, aggravate hyperlipidemia [79]. Moreover, Pasarín et al. found that the insulin-mediated phosphorylation of both Akt and eNOS was inhibited in rat LSECs, along with a blunted vasodilatory response to acetylcholine (ACh) [109]. In line, portal injection of insulin increased activation of eNOS in healthy rats but not those with MASLD [109]. Insulin resistance and impaired function in LSECs preceded any other sign of advanced MASLD in these rats [110]. The evidence indicates that LSEC dysfunction already occurs in early stages of MASLD and might contribute to the progression of the disease. Not only MASLD but also diabetes likely affects LSEC functionality since one study reported that fenestrae-porosity was significantly reduced in baboons with type 1 diabetes [111] and another showed that high glucose incubation led to capillarization of human primary LSECs in vitro [112].
The link between hypertension and MASLD has been well known [113,114], but the mechanism behind it is still obscure. As part of the vascular system, sinusoidal endothelium may also be affected by pro-hypertensive factors, contributing to portal hypertension and MASLD. Despite the lack of studies on the direct link between dysfunctional LSECs and hypertension, increasing evidence suggests a connection between portal hypertension and dysfunctional LSECs. A recent review demonstrated that intrahepatic vascular resistance and subsequent parenchymal hypoxia might be driving factors for MASLD [115]. In a recent study, van der Graaff et al. reported portal hypertension in the MASLD rat model induced by a methionine-choline-deficient diet (MCDD) that was mitigated by vasoconstrictor antagonism that even restored the structure of sinusoidal vasculature [116].

5. LSECs: An Interface Between the Intestine and Hepatocytes?

Recent studies have clearly shown that the composition of the gut microbiome differs between patients with MASLD and healthy subjects [6,117,118,119,120,121]. It is clear that certain species of bacteria contribute to the progression of MASLD [122,123,124,125] while bacteria that presumably likely provoke MASLD contribute to an impaired gut barrier, i.e., impairment of the epithelial barrier and the intestinal vascular barrier [126,127,128].
Emerging evidence suggests that the barrier function of the sinusoidal endothelium might also play a crucial role in the effects of the intestines on liver damage. Some studies reported that the profound effect of the intestinal barrier damage on the liver only occurs when the hepatic sinusoidal endothelial barrier is also impaired. For instance, although no independent correlation was found between inflammatory bowel disease (IBD) and liver stiffness [129] or fibrosis [130], IBD does aggravate the progress of pre-existing MASLD [131], thus likely in a situation where the sinusoidal epithelium is already dysfunctional. In line, one can speculate that a healthy LSEC barrier is crucial to protect the liver against gut-derived microbes and products.
Recent studies indeed suggest that capillarized LSECs play a mediatory role between gut bacteria and MASLD. The intestinal abundance of Escherichia coli was significantly increased in patients with MASLD compared to healthy controls, and supplementing E. coli to mice with diet-induced MASLD led to a transition of LSECs towards a more capillarized phenotype as well as aggravation of MASLD [132]. Similarly, Han et al. found that supplementation of beneficial bacteria attenuated hepatic damage by, amongst other methods, maintaining the integrity of the sinusoidal endothelium [133].
Though the direct correlation between gut commensal bacteria and LSECs is limited, multiple gut-derived products have been reported to affect the features and function of LSECs during MASLD progression. For instance, LPS, which innates immune response and promotes inflammation in the liver, has been found to be cleared mainly by LSECs [134]. Moreover, LPS reduces the number and diameter of fenestrae both in vitro [135] and in vivo [136,137] settings. In line, multiple studies demonstrated that LPS significantly impairs the LSEC function [136,138,139]. These findings strongly support LPS as the crucial mediator through which gut microbiota dysbiosis might induce LSEC dysfunction, thereby contributing to the progression of MASLD.
Another well-known pro-MASLD gut-derived factor is ethanol [140] that has been proven to induce LSEC dysfunction [141]. Also, bacteriophages that are among the most abundant biological entities in the gastrointestinal tract [142] are found to be degraded by LSECs [143]. The abundance of the Bacteroidetes phylum was inversely correlated with the porosity and diameter of fenestrae [35].
Beyond the study of the interplay between LSECs and gut microbial-derived products, there are some studies that reveal the effect of microbial metabolites on other endothelial cells. For instance, phenylacetylglutamine (PAGln), a co-metabolite from gut microbiota and host, was reported to accelerate cellular senescence of human umbilical vein endothelial cells (HUVECs) [144]. Though there is a lack of knowledge about the role of PAGln on LSECs, we can speculate that it is very likely that PAGln will also negatively affect LSEC functionality.
In general, research is focused on modulating the gut microbiome to improve MASLD by supplying beneficial microbes such as Anaerobutyricum soehngenii [9], Akkermansia muciniphila [145], and Bifidobacterium bifidum [146], or probiotics such as insoluble fibers [147], inulin [148], and oligofructose [149]. However, whether these microbes and probiotics also affect LSECs and therefore MASLD progression is not known and will require dedicated experiments in the future. These studies are, however, hampered by the lack of high-throughput biomarkers of LSEC functionality. Nowadays, we still have to rely on SEM to study LSEC physiology.

6. Conclusions

Taken together, LSECs have a pivotal contribution to the pathogenesis of MASLD, as summarized in Figure 1. Capillarization of LSEC drives the progression of MASLD by multiple mechanisms, of which reduced NO production, hampered filtration, and clearance functions are well-supported. In addition, emerging hypotheses suggest that LSEC capillarization may exacerbate MASLD by abnormal activation of KCs and HSCs, and by disturbing the vascular barrier integrity. Vice versa, MASLD affects LSEC physiology and function. Functional LSECs are necessary to protect the liver from gut-driven attacks, hence, LSECs can be a novel target to interfere in the gut–liver axis, particularly in MASLD. Several molecules, e.g., statins, VEGF, and BMP9, have been reported to protect LSECs against capillarization in vitro, indicating their potential for translational applications. Notably, their therapeutic potential requires further in vivo validation to investigate efficacy, but also to study potential effects on endothelial cells in organs other than the liver. However, such dedicated studies on LSEC functionality are hampered by the fact that this still depends on labor-intensive SEM, for which material is often lacking, especially in clinical studies in which only one small liver biopsy is collected.

Author Contributions

Conceptualization, A.G. and A.G.H; writing—original draft preparation, T.C.; writing—review and editing, A.G. and A.G.H. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Conflicts of Interest

The authors declare no conflicts of interest.

Abbreviations

The following abbreviations are used in this manuscript:
A2Mα2-Macroglobulin
AβAmyloid-β peptide
AChAcetylcholine
Ac-LDLAcetylated low-density lipoprotein
AGEsAdvanced glycation end products
ApoApolipoprotein
BMIBody mass index
BMP9Bone morphogenic protein 9
CDAACholine-deficient L-amino acid-defined
CTGFConnective tissue growth factor
ECMExtracellular matrix
FFAFree fatty acid
HAHyaluronan
HCVHepatitis C virus
HDLHigh-density lipoprotein
HFDHigh-fat diet
HMGB1High mobility group box 1
HSCHepatic stellate cell
HSPHeat shock protein
HUVECsHuman umbilical vein endothelial cells
IAPPIslet amyloid polypeptide
IBDInflammatory bowel disease
KCKupffer cell
LCFALong-chain fatty acid
LPALysophosphatidic acid
LPSLipopolysaccharides
LTALipoteichoic acid
LDLLow-density lipoprotein
LRP-1Low-density lipoprotein receptor-related protein-1
LSECLiver sinusoidal endothelial cell
MASHMetabolic dysfunction-associated steatohepatitis
MASLDMetabolic dysfunction-associated steatotic liver disease
MDAASBMalondialdehyde-acetaldehyde-serum albumin
NAFLDNon-alcoholic fatty liver disease
NONitric oxide
OPNOsteopontin
Ox-LDLOxidized low-density lipoprotein
PAGlnPhenylacetylglutamine
PAOPhosphorothioate antisense oligonucleotides
PICPProcollagen type I C-terminal propeptide
PLVAPPlasmalemma vesicle-associated protein
RAGEReceptor for advanced glycation end-products
SEMScanning electron microscopy
SRScavenger receptor
TGFβ1Transforming growth factor β-1
tPATissue plasminogen activator
TSP-1Thrombospondin-1
VEGFVascular endothelial growth factor
VLDLVery low-density lipoprotein

References

  1. Eslam, M.; Newsome, P.N.; Sarin, S.K.; Anstee, Q.M.; Targher, G.; Romero-Gomez, M.; Zelber-Sagi, S.; Wong, V.W.-S.; Dufour, J.F.; Schattenberg, J.M. A new definition for metabolic dysfunction-associated fatty liver disease: An international expert consensus statement. J. Hepatol. 2020, 73, 202–209. [Google Scholar] [CrossRef] [PubMed]
  2. Younossi, Z.M.; Golabi, P.; Paik, J.M.; Henry, A.; Van Dongen, C.; Henry, L. The global epidemiology of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH): A systematic review. Hepatology 2023, 77, 1335–1347. [Google Scholar] [CrossRef] [PubMed]
  3. Huang, D.Q.; Terrault, N.A.; Tacke, F.; Gluud, L.L.; Arrese, M.; Bugianesi, E.; Loomba, R. Global epidemiology of cirrhosis–Aetiology, trends and predictions. Nat. Rev. Gastroenterol. Hepatol. 2023, 20, 388–398. [Google Scholar] [CrossRef]
  4. Keam, S.J. Resmetirom: First Approval. Drugs 2024, 84, 729–735. [Google Scholar] [CrossRef]
  5. Harrison, S.A.; Bedossa, P.; Guy, C.D.; Schattenberg, J.M.; Loomba, R.; Taub, R.; Labriola, D.; Moussa, S.E.; Neff, G.W.; Rinella, M.E.; et al. A Phase Randomized, Controlled Trial of Resmetirom in NASH with Liver Fibrosis. N. Engl. J. Med. 2024, 390, 497–509. [Google Scholar] [CrossRef]
  6. Zhu, L.; Baker, S.S.; Gill, C.; Liu, W.; Alkhouri, R.; Baker, R.D.; Gill, S.R. Characterization of gut microbiomes in nonalcoholic steatohepatitis (NASH) patients: A connection between endogenous alcohol and NASH. Hepatology 2013, 57, 601–609. [Google Scholar] [CrossRef]
  7. Mouzaki, M.; Comelli, E.M.; Arendt, B.M.; Bonengel, J.; Fung, S.K.; Fischer, S.E.; McGilvray, I.D.; Allard, J.P. Intestinal microbiota in patients with nonalcoholic fatty liver disease. Hepatology 2013, 58, 120–127. [Google Scholar] [CrossRef]
  8. Da Silva, H.E.; Teterina, A.; Comelli, E.M.; Taibi, A.; Arendt, B.M.; Fischer, S.E.; Lou, W.; Allard, J.P. Nonalcoholic fatty liver disease is associated with dysbiosis independent of body mass index and insulin resistance. Sci. Rep. 2018, 8, 1466. [Google Scholar] [CrossRef]
  9. Mak, A.L.; Augustijn, Q.J.J.; Heymann, C.J.F.; Havik, S.; Verdoes, X.; Rios-Morales, M.; Bosmans, L.A.; Verheij, J.; Meijnikman, A.S.; de Jonge, P.A.; et al. Anaerobutyricum soehngenii Reduces Hepatic Lipogenic Pathways and Increases Intestinal Gluconeogenic Gene Expression in Metabolic-Dysfunction-Associated Steatotic Liver Disease (MASLD Mice). Int. J. Mol. Sci. 2024, 25, 3481. [Google Scholar] [CrossRef]
  10. Leung, H.; Long, X.; Ni, Y.; Qian, L.; Nychas, E.; Siliceo, S.L.; Pohl, D.; Hanhineva, K.; Liu, Y.; Xu, A. Risk assessment with gut microbiome and metabolite markers in NAFLD development. Sci. Transl. Med. 2022, 14, eabk0855. [Google Scholar] [CrossRef]
  11. Wallace, S.J.; Tacke, F.; Schwabe, R.F.; Henderson, N.C. Understanding the cellular interactome of non-alcoholic fatty liver disease. JHEP Rep. 2022, 4, 100524. [Google Scholar] [CrossRef] [PubMed]
  12. Su, Q.; Kim, S.Y.; Adewale, F.; Zhou, Y.; Aldler, C.; Ni, M.; Wei, Y.; Burczynski, M.E.; Atwal, G.S.; Sleeman, M.W. Single-cell RNA transcriptome landscape of hepatocytes and non-parenchymal cells in healthy and NAFLD mouse liver. iScience 2021, 24, 103233. [Google Scholar] [CrossRef] [PubMed]
  13. Poisson, J.; Lemoinne, S.; Boulanger, C.; Durand, F.; Moreau, R.; Valla, D.; Rautou, P.E. Liver sinusoidal endothelial cells: Physiology and role in liver diseases. J. Hepatol. 2017, 66, 212–227. [Google Scholar] [CrossRef] [PubMed]
  14. Miyao, M.; Kotani, H.; Ishida, T.; Kawai, C.; Manabe, S.; Abiru, H.; Tamaki, K. Pivotal role of liver sinusoidal endothelial cells in NAFLD/NASH progression. Lab. Investig. 2015, 95, 1130–1144. [Google Scholar] [CrossRef]
  15. Zhang, Q.; Yu, J.; Guo, T.; Tian, L.; Quan, J.; Lin, W.; Niu, X.E.; Liu, J. High glucose/ox-LDL induced hepatic sinusoidal capillarization via αvβ5/FAK/ERK signaling pathway. Biochem. Biophys. Res. Commun. 2019, 513, 1055–1062. [Google Scholar] [CrossRef]
  16. Peng, Q.; Zhang, Q.; Xiao, W.; Shao, M.; Fan, Q.; Zhang, H.; Zou, Y.; Li, X.; Xu, W.; Mo, Z. Protective effects of Sapindus mukorossi Gaertn against fatty liver disease induced by high fat diet in rats. Biochem. Biophys. Res. Commun. 2014, 450, 685–691. [Google Scholar] [CrossRef]
  17. Wright, P.L.; Smith, K.F.; Day, W.A.; Fraser, R. Small liver fenestrae may explain the susceptibility of rabbits to atherosclerosis. Arteriosclerosis 1983, 3, 344–348. [Google Scholar] [CrossRef]
  18. Wang, Y.; Liu, Y. Gut-liver-axis: Barrier function of liver sinusoidal endothelial cell. J. Gastroenterol. Hepatol. 2021, 36, 2706–2714. [Google Scholar] [CrossRef]
  19. Sørensen, K.K.; Simon-Santamaria, J.; McCuskey, R.S.; Smedsrød, B. Liver Sinusoidal Endothelial Cells. Compr. Physiol. 2015, 5, 1751–1774. [Google Scholar] [CrossRef]
  20. Smedsrød, B.; Melkko, J.; Araki, N.; Sano, H.; Horiuchi, S. Advanced glycation end products are eliminated by scavenger-receptor-mediated endocytosis in hepatic sinusoidal Kupffer and endothelial cells. Biochem. J. 1997, 322, 567–573. [Google Scholar] [CrossRef]
  21. DeLeve, L.D.; Maretti-Mira, A.C. Liver Sinusoidal Endothelial Cell: An Update. Semin. Liver. Dis. 2017, 37, 377–387. [Google Scholar] [PubMed]
  22. Braet, F.; Wisse, E. Structural and functional aspects of liver sinusoidal endothelial cell fenestrae: A review. Comp. Hepatol. 2002, 1, 1. [Google Scholar] [CrossRef] [PubMed]
  23. Fraser, R.; Cogger, V.C.; Dobbs, B.; Jamieson, H.; Warren, A.; Hilmer, S.N.; Le Couteur, D.G. The liver sieve and atherosclerosis. Pathology 2012, 44, 181–186. [Google Scholar] [CrossRef]
  24. Fraser, R.; Dobbs, B.R.; Rogers, G.W. Lipoproteins and the liver sieve: The role of the fenestrated sinusoidal endothelium in lipoprotein metabolism, atherosclerosis, and cirrhosis. Hepatology 1995, 21, 863–874. [Google Scholar]
  25. Cogger, V.C.; Hilmer, S.N.; Sullivan, D.; Muller, M.; Fraser, R.; Le Couteur, D.G. Hyperlipidemia and surfactants: The liver sieve is a link. Atherosclerosis 2006, 189, 273–281. [Google Scholar] [CrossRef]
  26. Wisse, E.; De Zanger, R.B.; Charels, K.; Van Der Smissen, P.; McCuskey, R.S. The liver sieve: Considerations concerning the structure and function of endothelial fenestrae, the sinusoidal wall and the space of Disse. Hepatology 1985, 5, 683–692. [Google Scholar] [CrossRef]
  27. Ribatti, D. Liver angiocrine factors. Tissue Cell 2023, 81, 102027. [Google Scholar] [CrossRef]
  28. Panday, R.; Monckton, C.P.; Khetani, S.R. The Role of Liver Zonation in Physiology, Regeneration, and Disease. Semin. Liver Dis. 2022, 42, 1–16. [Google Scholar] [CrossRef]
  29. Santos, A.A.; Delgado, T.C.; Marques, V.; Ramirez-Moncayo, C.; Alonso, C.; Vidal-Puig, A.; Hall, Z.; Martínez-Chantar, M.L.; Rodrigues, C.M.P. Spatial metabolomics and its application in the liver. Hepatology 2024, 79, 1158–1179. [Google Scholar] [CrossRef]
  30. Szafranska, K.; Kruse, L.D.; Holte, C.F.; McCourt, P.; Zapotoczny, B. The wHole Story About Fenestrations in LSEC. Front. Physiol. 2021, 12, 735573. [Google Scholar] [CrossRef]
  31. Eberhard, D.; Balkenhol, S.; Köster, A.; Follert, P.; Upschulte, E.; Ostermann, P.; Kirschner, P.; Uhlemeyer, C.; Charnay, I.; Preuss, C.; et al. Semaphorin-3A regulates liver sinusoidal endothelial cell porosity and promotes hepatic steatosis. Nat. Cardiovasc. Res. 2024, 3, 734–753. [Google Scholar] [CrossRef] [PubMed]
  32. Zhang, Q.; Liu, J.; Liu, J.; Huang, W.; Tian, L.; Quan, J.; Wang, Y.; Niu, R. oxLDL induces injury and defenestration of human liver sinusoidal endothelial cells via LOX1. J. Mol. Endocrinol. 2014, 53, 281–293. [Google Scholar] [CrossRef] [PubMed]
  33. Le Couteur, D.G.; Fraser, R.; Cogger, V.C.; McLean, A.J. Hepatic pseudocapillarisation and atherosclerosis in ageing. Lancet 2002, 359, 1612–1615. [Google Scholar] [CrossRef]
  34. Horn, T.; Christoffersen, P.; Henriksen, J.H. Alcoholic liver injury: Defenestration in noncirrhotic livers--a scanning electron microscopic study. Hepatology 1987, 7, 77–82. [Google Scholar] [CrossRef]
  35. Cogger, V.C.; Mohamad, M.; Solon-Biet, S.M.; Senior, A.M.; Warren, A.; O’Reilly, J.N.; Tung, B.T.; Svistounov, D.; McMahon, A.C.; Fraser, R.; et al. Dietary macronutrients and the aging liver sinusoidal endothelial cell. Am. J. Physiol. Heart Circ. Physiol. 2016, 310, H1064–H10670. [Google Scholar] [CrossRef]
  36. Desroches-Castan, A.; Tillet, E.; Ricard, N.; Ouarné, M.; Mallet, C.; Belmudes, L.; Couté, Y.; Boillot, O.; Scoazec, J.Y.; Bailly, S. Bone Morphogenetic Protein 9 Is a Paracrine Factor Controlling Liver Sinusoidal Endothelial Cell Fenestration and Protecting Against Hepatic Fibrosis. Hepatology 2019, 70, 1392–1408. [Google Scholar] [CrossRef]
  37. Shah, V.; Haddad, F.G.; Garcia-Cardena, G.; Frangos, J.A.; Mennone, A.; Groszmann, R.J.; Sessa, W.C. Liver sinusoidal endothelial cells are responsible for nitric oxide modulation of resistance in the hepatic sinusoids. J. Clin. Investig. 1997, 100, 2923–2930. [Google Scholar] [CrossRef]
  38. Carpenter, B.; Lin, Y.; Stoll, S.; Raffai, R.L.; McCuskey, R.; Wang, R. VEGF is crucial for the hepatic vascular development required for lipoprotein uptake. Development 2005, 132, 3293–3303. [Google Scholar] [CrossRef]
  39. Funyu, J.; Mochida, S.; Inao, M.; Matsui, A.; Fujiwara, K. VEGF Can Act as Vascular Permeability Factor in the Hepatic Sinusoids through Upregulation of Porosity of Endothelial Cells. Biochem. Biophys. Res. Commun. 2001, 280, 481–485. [Google Scholar] [CrossRef]
  40. Xie, G.; Wang, X.; Wang, L.; Wang, L.; Atkinson, R.D.; Kanel, G.C.; Gaarde, W.A.; DeLeve, L.D. Role of Differentiation of Liver Sinusoidal Endothelial Cells in Progression and Regression of Hepatic Fibrosis in Rats. Gastroenterology 2012, 142, 918–927.e6. [Google Scholar] [CrossRef]
  41. DeLeve, L.D.; Wang, X.; Hu, L.; McCuskey, M.K.; McCuskey, R.S. Rat liver sinusoidal endothelial cell phenotype is maintained by paracrine and autocrine regulation. Am. J. Physiol. Gastrointest. Liver. Physiol. 2004, 28, G757–G763. [Google Scholar] [CrossRef] [PubMed]
  42. Luo, X.; Wang, D.; Zhu, X.; Wang, G.; You, Y.; Ning, Z.; Li, Y.; Jin, S.; Huang, Y.; Hu, Y. Autophagic degradation of caveolin-1 promotes liver sinusoidal endothelial cells defenestration. Cell Death Dis. 2018, 9, 576. [Google Scholar] [CrossRef] [PubMed]
  43. Akaike, T.; Okamoto, S.; Sawa, T.; Yoshitake, J.; Tamura, F.; Ichimori, K.; Miyazaki, K.; Sasamoto, K.; Maeda, H. 8-nitroguanosine formation in viral pneumonia and its implication for pathogenesis. Proc. Natl. Acad. Sci. USA 2003, 100, 685–690. [Google Scholar] [CrossRef]
  44. Carnovale, C.E.; Ronco, M.T. Role of nitric oxide in liver regeneration. Ann. Hepatol. 2012, 11, 636–647. [Google Scholar] [CrossRef]
  45. McNaughton, L.; Puttagunta, L.; Martinez-Cuesta, M.A.; Kneteman, N.; Mayers, I.; Moqbel, R.; Hamid, Q.; Radomski, M.W. Distribution of nitric oxide synthase in normal and cirrhotic human liver. Proc. Natl. Acad. Sci. USA 2002, 99, 17161–17166. [Google Scholar] [CrossRef]
  46. Su, T.; Yang, Y.; Lai, S.; Jeong, J.; Jung, Y.; McConnell, M.; Utsumi, T.; Iwakiri, Y. Single-Cell Transcriptomics Reveals Zone-Specific Alterations of Liver Sinusoidal Endothelial Cells in Cirrhosis. Cell. Mol. Gastroenterol. Hepatol. 2021, 11, 1139–1161. [Google Scholar] [CrossRef]
  47. Smedsrød, B. Clearance function of scavenger endothelial cells. Comp. Hepatol. 2004, 3 (Suppl. S1), S22. [Google Scholar] [CrossRef]
  48. Wang, Y.; Zhang, Y.; Liu, Y.; Xu, J.; Liu, Y. Gut-Liver Axis: Liver Sinusoidal Endothelial Cells Function as the Hepatic Barrier in Colitis-Induced Liver Injury. Front. Cell Dev. Biol. 2021, 9, 702890. [Google Scholar] [CrossRef]
  49. Pandey, E.; Nour, A.S.; Harris, E.N. Prominent Receptors of Liver Sinusoidal Endothelial Cells in Liver Homeostasis and Disease. Front. Physiol. 2020, 11, 873. [Google Scholar] [CrossRef]
  50. Alquraini, A.; El Khoury, J. Scavenger receptors. Curr. Biol. 2020, 30, R790–R795. [Google Scholar] [CrossRef]
  51. Malovic, I.; Sφrensen, K.K.; Elvevold, K.H.; Nedredal, G.I.; Paulsen, S.; Erofeev, A.V.; Smedsr, B.H.; McCourt, P.A.G. The mannose receptor on murine liver sinusoidal endothelial cells is the main denatured collagen clearance receptor. Hepatology 2007, 45, 1454–1461. [Google Scholar] [CrossRef] [PubMed]
  52. Smedsrød, B.; Melkko, J.; Risteli, L.; Risteli, J. Circulating C-terminal propeptide of type I procollagen is cleared mainly via the mannose receptor in liver endothelial cells. Biochem. J. 1990, 271, 345–350. [Google Scholar] [CrossRef] [PubMed]
  53. de Haan, W.; Øie, C.; Benkheil, M.; Dheedene, W.; Vinckier, S.; Coppiello, G.; Aranguren, X.L.; Beerens, M.; Jaekers, J.; Topal, B.; et al. Unraveling the transcriptional determinants of liver sinusoidal endothelial cell specialization. Am. J. Physiol. Gastrointest. Liver Physiol. 2020, 318, G803–G815. [Google Scholar] [CrossRef] [PubMed]
  54. Hubbard, A.L.; Wilson, G.; Ashwell, G.; Stukenbrok, H. An electron microscope autoradiographic study of the carbohydrate recognition systems in rat liver. I. Distribution of 125I-ligands among the liver cell types. J. Cell. Biol. 1979, 83, 47–64. [Google Scholar]
  55. Elvevold, K.; Simon-Santamaria, J.; Hasvold, H.; McCourt, P.; Smedsrød, B.; Sørensen, K.K. Liver sinusoidal endothelial cells depend on mannose receptor-mediated recruitment of lysosomal enzymes for normal degradation capacity. Hepatology 2008, 48, 2007–2015. [Google Scholar] [CrossRef]
  56. PrabhuDas, M.R.; Baldwin, C.L.; Bollyky, P.L.; Bowdish, D.M.E.; Drickamer, K.; Febbraio, M.; Herz, J.; Kobzik, L.; Krieger, M.; Loike, J.; et al. A Consensus Definitive Classification of Scavenger Receptors and Their Roles in Health and Disease. J. Immunol. 2017, 198, 3775–3789. [Google Scholar] [CrossRef]
  57. Van Berkel, T.J.; De Rijke, Y.B.; Kruijt, J.K. Different fate in vivo of oxidatively modified low density lipoprotein and acetylated low density lipoprotein in rats. Recognition by various scavenger receptors on Kupffer and endothelial liver cells. J. Biol. Chem. 1991, 266, 2282–2289. [Google Scholar] [CrossRef]
  58. Nagelkerke, J.F.; Barto, K.P.; van Berkel, T.J. In vivo and in vitro uptake and degradation of acetylated low density lipoprotein by rat liver endothelial, Kupffer, and parenchymal cells. J. Biol. Chem. 1983, 258, 12221–12227. [Google Scholar] [CrossRef]
  59. Shen, W.J.; Azhar, S.; Kraemer, F.B. SR-B1: A Unique Multifunctional Receptor for Cholesterol Influx and Efflux. Annu. Rev. Physiol. 2018, 80, 95–116. [Google Scholar] [CrossRef]
  60. Strauss, O.; Phillips, A.; Ruggiero, K.; Bartlett, A.; Dunbar, P.R. Immunofluorescence identifies distinct subsets of endothelial cells in the human liver. Sci. Rep. 2017, 7, 44356. [Google Scholar] [CrossRef]
  61. Coburn, C.T.; Knapp, F.F., Jr.; Febbraio, M.; Beets, A.L.; Silverstein, R.L.; Abumrad, N.A. Defective uptake and utilization of long chain fatty acids in muscle and adipose tissues of CD36 knockout mice. J. Biol. Chem. 2000, 275, 32523–32529. [Google Scholar] [PubMed]
  62. Brundert, M.; Heeren, J.; Merkel, M.; Carambia, A.; Herkel, J.; Groitl, P.; Dobner, T.; Ramakrishnan, R.; Moore, K.J.; Rinninger, F. Scavenger receptor CD36 mediates uptake of high density lipoproteins in mice and by cultured cells. J. Lipid Res. 2011, 52, 745–758. [Google Scholar] [CrossRef] [PubMed]
  63. Son, N.H.; Basu, D.; Samovski, D.; Pietka, T.A.; Peche, V.S.; Willecke, F.; Fang, X.; Yu, S.Q.; Scerbo, D.; Chang, H.R.; et al. Endothelial cell CD36 optimizes tissue fatty acid uptake. J. Clin. Investig. 2018, 128, 4329–4342. [Google Scholar] [CrossRef]
  64. Li, R.; Oteiza, A.; Sørensen, K.K.; McCourt, P.; Olsen, R.; Smedsrød, B.; Svistounov, D. Role of liver sinusoidal endothelial cells and stabilins in elimination of oxidized low-density lipoproteins. Am. J. Physiol. Gastrointest. Liver. Physiol. 2011, 300, G71–G81. [Google Scholar] [CrossRef]
  65. van de Sluis, B.; Wijers, M.; Herz, J. News on the molecular regulation and function of hepatic low-density lipoprotein receptor and LDLR-related protein 1. Curr. Opin. Lipidol. 2017, 28, 241–247. [Google Scholar]
  66. Ding, Y.; Xian, X.; Holland, W.L.; Tsai, S.; Herz, J. Low-Density Lipoprotein Receptor-Related Protein-1 Protects Against Hepatic Insulin Resistance and Hepatic Steatosis. EBioMedicine 2016, 7, 135–145. [Google Scholar]
  67. Pereira, E.; Paula, D.P.; de Araujo, B.P.; da Fonseca, M.J.M.; Diniz, M.; Daliry, A.; Griep, R.H. Advanced glycation end product: A potential biomarker for risk stratification of non-alcoholic fatty liver disease in ELSA-Brasil study. World J. Gastroenterol. 2021, 27, 4913–4928. [Google Scholar] [CrossRef]
  68. Leung, C.; Herath, C.B.; Jia, Z.; Andrikopoulos, S.; Brown, B.E.; Davies, M.J.; Rivera, L.R.; Furness, J.B.; Forbes, J.M.; Angus, P.W. Dietary advanced glycation end-products aggravate non-alcoholic fatty liver disease. World J. Gastroenterol. 2016, 22, 8026–8040. [Google Scholar] [CrossRef]
  69. Arias-Alpizar, G.; Koch, B.; Hamelmann, N.M.; Neustrup, M.A.; Paulusse, J.M.J.; Jiskoot, W.; Kros, A.; Bussmann, J. Stabilin-1 is required for the endothelial clearance of small anionic nanoparticles. Nanomedicine 2021, 34, 102395. [Google Scholar]
  70. Li, R.; McCourt, P.; Schledzewski, K.; Goerdt, S.; Moldenhauer, G.; Liu, X.; Smedsrød, B.; Sørensen, K.K. Endocytosis of advanced glycation end-products in bovine choriocapillaris endothelial cells. Microcirculation 2009, 16, 640–655. [Google Scholar] [CrossRef]
  71. Lohwasser, C.; Neureiter, D.; Popov, Y.; Bauer, M.; Schuppan, D. Role of the receptor for advanced glycation end products in hepatic fibrosis. World J. Gastroenterol. 2009, 15, 5789–5798. [Google Scholar] [PubMed]
  72. An, L.; Wirth, U.; Koch, D.; Schirren, M.; Drefs, M.; Koliogiannis, D.; Nieß, H.; Andrassy, J.; Guba, M.; Bazhin, A.V.; et al. The Role of Gut-Derived Lipopolysaccharides and the Intestinal Barrier in Fatty Liver Diseases. J. Gastrointest. Surg. 2022, 26, 671–683. [Google Scholar] [CrossRef] [PubMed]
  73. Olsavszky, V.; Sticht, C.; Schmid, C.D.; Winkler, M.; Wohlfeil, S.A.; Olsavszky, A.; Schledzewski, K.; Géraud, C.; Goerdt, S.; Leibing, T. Exploring the transcriptomic network of multi-ligand scavenger receptor Stabilin-1- and Stabilin-2-deficient liver sinusoidal endothelial cells. Gene 2021, 768, 145284. [Google Scholar] [CrossRef] [PubMed]
  74. Cabral, F.; Al-Rahem, M.; Skaggs, J.; Thomas, T.A.; Kumar, N.; Wu, Q.; Fadda, P.; Yu, L.; Robinson, J.M.; Kim, J.; et al. Stabilin receptors clear LPS and control systemic inflammation. iScience 2021, 24, 103337. [Google Scholar] [CrossRef]
  75. McDonald, B.; McAvoy, E.F.; Lam, F.; Gill, V.; de la Motte, C.; Savani, R.C.; Kubes, P. Interaction of CD44 and hyaluronan is the dominant mechanism for neutrophil sequestration in inflamed liver sinusoids. J. Exp. Med. 2008, 205, 915–927. [Google Scholar] [CrossRef]
  76. Zeuzem, S. Gut-liver axis. Int. J. Colorectal. Dis. 2000, 15, 59–82. [Google Scholar]
  77. Pugin, J.; Chevrolet, J.C. The intestine-liver-lung axis in septic syndrome. Schweiz Med. Wochenschr. 1991, 121, 1538–1544. [Google Scholar]
  78. Leung, C.; Rivera, L.; Furness, J.B.; Angus, P.W. The role of the gut microbiota in NAFLD. Nat. Rev. Gastroenterol. Hepatol. 2016, 13, 412–425. [Google Scholar]
  79. Hammoutene, A.; Rautou, P.E. Role of liver sinusoidal endothelial cells in non-alcoholic fatty liver disease. J. Hepatol. 2019, 70, 1278–1291. [Google Scholar]
  80. Jensen, M.D.; Nielsen, S. Insulin dose response analysis of free fatty acid kinetics. Metab. Clin. Exp. 2007, 56, 68–76. [Google Scholar] [CrossRef]
  81. Bansal, S.K.; Bansal, M.B. Pathogenesis of MASLD and MASH–role of insulin resistance and lipotoxicity. Aliment. Pharmacol. Ther. 2024, 59 (Suppl. S1), S10–S22. [Google Scholar] [CrossRef] [PubMed]
  82. Donnelly, K.L.; Smith, C.I.; Schwarzenberg, S.J.; Jessurun, J.; Boldt, M.D.; Parks, E.J. Sources of fatty acids stored in liver and secreted via lipoproteins in patients with nonalcoholic fatty liver disease. J. Clin. Investig. 2005, 115, 1343–1351. [Google Scholar] [CrossRef] [PubMed]
  83. Wree, A.; Schlattjan, M.; Bechmann, L.P.; Claudel, T.; Sowa, J.P.; Stojakovic, T.; Scharnagl, H.; Köfeler, H.; Baba, H.A.; Gerken, G. Adipocyte cell size, free fatty acids and apolipoproteins are associated with non-alcoholic liver injury progression in severely obese patients. Metab. Clin. Exp. 2014, 63, 1542–1552. [Google Scholar] [CrossRef]
  84. Hang, T.C.; Lauffenburger, D.A.; Griffith, L.G.; Stolz, D.B. Lipids promote survival; proliferation, and maintenance of differentiation of rat liver sinusoidal endothelial cells in vitro. Am. J. Physiol. Gastrointest. Liver. Physiol. 2012, 302, G375–G388. [Google Scholar] [CrossRef]
  85. Fang, Z.Q.; Ruan, B.; Liu, J.J.; Duan, J.L.; Yue, Z.S.; Song, P.; Xu, H.; Ding, J.; Xu, C.; Dou, G.R. Notch-triggered maladaptation of liver sinusoidal endothelium aggravates nonalcoholic steatohepatitis through endothelial nitric oxide synthase. Hepatology 2022, 76, 742–758. [Google Scholar] [CrossRef]
  86. Jung, E.; Baek, E.B.; Hong, E.J.; Kang, J.H.; Park, S.; Park, S.; Hong, E.J.; Cho, Y.E.; Ko, J.W.; Won, Y.S. TXNIP in liver sinusoidal endothelial cells ameliorates alcohol-associated liver disease via nitric oxide production. Int. J. Biol. Sci. 2024, 20, 606–620. [Google Scholar] [CrossRef]
  87. Ni, Y.; Li, J.M.; Liu, M.K.; Zhang, T.T.; Wang, D.P.; Zhou, W.H.; Hu, L.Z.; Lv, W.L. Pathological process of liver sinusoidal endothelial cells in liver diseases. World J. Gastroenterol. 2017, 23, 7666–7677. [Google Scholar] [CrossRef]
  88. Gao, J.; Zuo, B.; He, Y. Liver sinusoidal endothelial cells as potential drivers of liver fibrosis Review. Mol. Med. Rep. 2024, 29, 40. [Google Scholar] [CrossRef]
  89. Wiering, L.; Subramanian, P.; Hammerich, L. Hepatic Stellate Cells: Dictating Outcome in Nonalcoholic Fatty Liver Disease. Cell. Mol. Gastroenterol. Hepatol. 2023, 15, 1277–1292. [Google Scholar] [CrossRef]
  90. Xu, G.X.; Wei, S.; Yu, C.; Zhao, S.Q.; Yang, W.J.; Feng, Y.H.; Pan, C.; Yang, K.X.; Ma, Y. Activation of Kupffer cells in NAFLD and NASH: Mechanisms and therapeutic interventions. Front Cell Dev. Biol. 2023, 11, 1199519. [Google Scholar] [CrossRef]
  91. Gordon, L.; Blechman, J.; Shimoni, E.; Gur, D.; Anand-Apte, B.; Levkowitz, G. The fenestrae-associated protein Plvap regulates the rate of blood-borne protein passage into the hypophysis. Development 2019, 146, dev177790. [Google Scholar] [CrossRef] [PubMed]
  92. Herrnberger, L.; Hennig, R.; Kremer, W.; Hellerbrand, C.; Goepferich, A.; Kalbitzer, H.R.; Tamm, E.R. Formation of fenestrae in murine liver sinusoids depends on plasmalemma vesicle-associated protein and is required for lipoprotein passage. PLoS ONE 2014, 9, e115005. [Google Scholar] [CrossRef]
  93. Maslak, E.; Gregorius, A.; Chlopicki, S. Liver sinusoidal endothelial cells LSECs function and NAFLD.; NO-based therapy targeted to the liver. Pharmacol. Rep. 2015, 67, 689–694. [Google Scholar] [CrossRef] [PubMed]
  94. Rockey, D.C.; Chung, J.J. Reduced nitric oxide production by endothelial cells in cirrhotic rat liver: Endothelial dysfunction in portal hypertension. Gastroenterology 1998, 114, 344–351. [Google Scholar] [CrossRef]
  95. Sato, I.; Yamamoto, S.; Kakimoto, M.; Fujii, M.; Honma, K.; Kumazaki, S.; Matsui, M.; Nakayama, H.; Kirihara, S.; Ran, S.; et al. Suppression of nitric oxide synthase aggravates non-alcoholic steatohepatitis and atherosclerosis in SHRSP5/Dmcr rat via acceleration of abnormal lipid metabolism. Pharmacol. Rep. 2022, 74, 669–683. [Google Scholar] [CrossRef]
  96. Schild, L.; Dombrowski, F.; Lendeckel, U.; Schulz, C.; Gardemann, A.; Keilhoff, G. Impairment of endothelial nitric oxide synthase causes abnormal fat and glycogen deposition in liver. Biochim. Biophys. Acta BBA–Mol. Basis Dis. 2008, 1782, 180–187. [Google Scholar] [CrossRef]
  97. Nozaki, Y.; Fujita, K.; Wada, K.; Yoneda, M.; Shinohara, Y.; Imajo, K.; Ogawa, Y.; Kessoku, T.; Nakamuta, M.; Saito, S.; et al. Deficiency of eNOS exacerbates early-stage NAFLD pathogenesis by changing the fat distribution. BMC Gastroenterol. 2015, 15, 177. [Google Scholar] [CrossRef]
  98. Sheldon, R.D.; Meers, G.M.; Morris, E.M.; Linden, M.A.; Cunningham, R.P.; Ibdah, J.A.; Thyfault, J.P.; Laughlin, M.H.; Rector, R.S. eNOS deletion impairs mitochondrial quality control and exacerbates Western diet-induced NASH. Am. J. Physiol. Endocrinol. Metab. 2019, 317, E605–E616. [Google Scholar] [CrossRef]
  99. Ahsan, F.; Oliveri, F.; Goud, H.K.; Mehkari, Z.; Mohammed, L.; Javed, M.; Althwanay, A.; Rutkofsky, I.H. Pleiotropic Effects of Statins in the Light of Non-Alcoholic Fatty Liver Disease and Non-Alcoholic Steatohepatitis. Cureus 2020, 12, e10446. [Google Scholar] [CrossRef]
  100. Guo, W.; Li, Z.; Anagnostopoulos, G.; Kong, W.T.; Zhang, S.; Chakarov, S.; Shin, A.; Qian, J.; Zhu, Y.; Bai, W.; et al. Notch signaling regulates macrophage-mediated inflammation in metabolic dysfunction-associated steatotic liver disease. Immunity 2024, 57, 2310–2327.e6. [Google Scholar] [CrossRef] [PubMed]
  101. Minciuna, I.; Taru, M.G.; Procopet, B.; Stefanescu, H. The Interplay between Liver Sinusoidal Endothelial Cells, Platelets, and Neutrophil Extracellular Traps in the Development and Progression of Metabolic Dysfunction-Associated Steatotic Liver Disease. J. Clin. Med. 2024, 13, 1406. [Google Scholar] [CrossRef] [PubMed]
  102. Luo, W.; Xu, Q.; Wang, Q.; Wu, H.; Hua, J. Effect of modulation of PPAR-γ activity on Kupffer cells M1/M2 polarization in the development of non-alcoholic fatty liver disease. Sci. Rep. 2017, 7, 44612. [Google Scholar] [CrossRef] [PubMed]
  103. Tateya, S.; Rizzo, N.O.; Handa, P.; Cheng, A.M.; Morgan-Stevenson, V.; Daum, G.; Clowes, A.W.; Morton, G.J.; Schwartz, M.W.; Kim, F. Endothelial NO/cGMP/VASP Signaling Attenuates Kupffer Cell Activation and Hepatic Insulin Resistance Induced by High-Fat Feeding. Diabetes 2011, 60, 2792–2801. [Google Scholar] [CrossRef]
  104. Lee, W.J.; Tateya, S.; Cheng, A.M.; Rizzo-DeLeon, N.; Wang, N.F.; Handa, P.; Wilson, C.L.; Clowes, A.W.; Sweet, I.R.; Bomsztyk, K. M2 Macrophage Polarization Mediates Anti-inflammatory Effects of Endothelial Nitric Oxide Signaling. Diabetes 2015, 64, 2836–2846. [Google Scholar] [CrossRef]
  105. Wang, J.; Wu, Z.; Xia, M.; Salas, S.S.; Ospina, J.A.; Buist-Homan, M.; Harmsen, M.C.; Moshage, H. Extracellular vesicles derived from liver sinusoidal endothelial cells inhibit the activation of hepatic stellate cells and Kupffer cells in vitro. Biochim. Biophys. Acta. Mol. Basis. Dis. 2024, 1870, 167020. [Google Scholar] [CrossRef]
  106. Tsuchiya, K.; Accili, D. Liver Sinusoidal Endothelial Cells Link Hyperinsulinemia to Hepatic Insulin Resistance. Diabetes 2013, 62, 1478–1489. [Google Scholar] [CrossRef]
  107. Wang, M.; Li, L.; Xu, Y.; Du, J.; Ling, C. Roles of hepatic stellate cells in NAFLD: From the perspective of inflammation and fibrosis. Front. Pharmacol. 2022, 13, 958428. [Google Scholar] [CrossRef]
  108. Schwabe, R.F.; Tabas, I.; Pajvani, U.B. Mechanisms of Fibrosis Development in Nonalcoholic Steatohepatitis. Gastroenterology 2020, 158, 1913–1928. [Google Scholar] [CrossRef]
  109. Pasarín, M.; La Mura, V.; Gracia-Sancho, J.; García-Calderó, H.; Rodríguez-Vilarrupla, A.; García-Pagán, J.C.; Bosch, J.; Abraldes, J.G. Sinusoidal endothelial dysfunction precedes inflammation and fibrosis in a model of NAFLD. PLoS ONE 2012, 7, e32785. [Google Scholar] [CrossRef]
  110. Pasarín, M.; Abraldes, J.G.; Rodríguez-Vilarrupla, A.; La Mura, V.; García-Pagán, J.C.; Bosch, J. Insulin resistance and liver microcirculation in a rat model of early NAFLD. J. Hepatol. 2011, 55, 1095–1102. [Google Scholar] [CrossRef]
  111. Jamieson, H.A.; Cogger, V.C.; Twigg, S.M.; McLennan, S.V.; Warren, A.; Cheluvappa, R.; Hilmer, S.N.; Fraser, R.; de Cabo, R.; Le Couteur, D.G. Alterations in liver sinusoidal endothelium in a baboon model of type 1 diabetes. Diabetologia 2007, 50, 1969–1976. [Google Scholar] [CrossRef] [PubMed]
  112. Liu, J.; Quan, J.; Feng, J.; Zhang, Q.; Xu, Y.; Liu, J.; Huang, W.; Liu, J.; Tian, L. High glucose regulates LN expression in human liver sinusoidal endothelial cells through ROS/integrin αvβ3 pathway. Environ. Toxicol. Pharmacol. 2016, 42, 231–236. [Google Scholar] [CrossRef] [PubMed]
  113. Lonardo, A.; Nascimbeni, F.; Mantovani, A.; Targher, G. Hypertension; diabetes; atherosclerosis. Hepatol. J. 2018, 68, 335–352. [Google Scholar] [CrossRef]
  114. Loomba, R.; Wong, R.; Fraysse, J.; Shreay, S.; Li, S.; Harrison, S.; Gordon, S.C. Nonalcoholic fatty liver disease progression rates to cirrhosis and progression of cirrhosis to decompensation and mortality: A real world analysis of Medicare data. Aliment. Pharmacol. Ther. 2020, 51, 1149–1159. [Google Scholar] [CrossRef]
  115. van der Graaff, D.; Kwanten, W.J.; Francque, S.M. The potential role of vascular alterations and subsequent impaired liver blood flow and hepatic hypoxia in the pathophysiology of non-alcoholic steatohepatitis. Med. Hypotheses 2019, 122, 188–197. [Google Scholar] [CrossRef]
  116. van der Graaff, D.; Chotkoe, S.; De Winter, B.; De Man, J.; Casteleyn, C.; Timmermans, J.P.; Pintelon, I.; Vonghia, L.; Kwanten, W.J.; Francque, S. Vasoconstrictor antagonism improves functional and structural vascular alterations and liver damage in rats with early NAFLD. JHEP Rep. 2022, 4, 100412. [Google Scholar] [CrossRef]
  117. Safari, Z.; Gérard, P. The links between the gut microbiome and non-alcoholic fatty liver disease NAFLD. Cell. Mol. Life Sci. 2019, 76, 1541–1558. [Google Scholar] [CrossRef]
  118. Poeta, M.; Pierri, L.; Vajro, P. Gut-Liver Axis Derangement in Non-Alcoholic Fatty Liver Disease. Children 2017, 4, 66. [Google Scholar] [CrossRef]
  119. Miele, L.; Valenza, V.; La Torre, G.; Montalto, M.; Cammarota, G.; Ricci, R.; Mascianà, R.; Forgione, A.; Gabrieli, M.L.; Perotti, G.; et al. Increased intestinal permeability and tight junction alterations in nonalcoholic fatty liver disease. Hepatol. Baltim. Md. 2009, 49, 1877–1887. [Google Scholar] [CrossRef]
  120. Henao-Mejia, J.; Elinav, E.; Jin, C.; Hao, L.; Mehal, W.Z.; Strowig, T.; Thaiss, C.A.; Kau, A.L.; Eisenbarth, S.C.; Jurczak, M.J.; et al. Inflammasome-mediated dysbiosis regulates progression of NAFLD and obesity. Nature 2012, 482, 179–185. [Google Scholar] [CrossRef]
  121. Raman, M.; Ahmed, I.; Gillevet, P.M.; Probert, C.S.; Ratcliffe, N.M.; Smith, S.; Greenwood, R.; Sikaroodi, M.; Lam, V.; Crotty, P. Fecal microbiome and volatile organic compound metabolome in obese humans with nonalcoholic fatty liver disease. Clinical gastroenterology and hepatology. Off. Clin. Pract. J. Am. Gastroenterol. Assoc. 2013, 11, e1–e3. [Google Scholar]
  122. Cornejo-Pareja, I.; Amiar, M.R.; Ocaña-Wilhelmi, L.; Soler-Humanes, R.; Arranz-Salas, I.; Garrido-Sánchez, L.; Gutiérrez-Repiso, C.; Tinahones, F.J. Non-alcoholic fatty liver disease in patients with morbid obesity: The gut microbiota axis as a potential pathophysiology mechanism. J. Gastroenterol. 2024, 59, 329–341. [Google Scholar] [CrossRef] [PubMed]
  123. Chu, H.; Duan, Y.; Yang, L.; Schnabl, B. Small metabolites, possible big changes: A microbiota-centered view of non-alcoholic fatty liver disease. Gut 2019, 68, 359–370. [Google Scholar] [CrossRef]
  124. Yuan, J.; Chen, C.; Cui, J.; Lu, J.; Yan, C.; Wei, X.; Zhao, X.; Li, N.; Li, S.; Xue, G.; et al. Fatty Liver Disease Caused by High-Alcohol-Producing Klebsiella pneumoniae. Cell Metab. 2019, 30, 675–688.e7. [Google Scholar] [CrossRef]
  125. Jadhav, K.; Cohen, T.S. Can You Trust Your Gut? Implicating a Disrupted Intestinal Microbiome in the Progression of NAFLD/NASH. Front. Endocrinol Lausanne 2020, 11, 592157. [Google Scholar] [CrossRef]
  126. Mouries, J.; Brescia, P.; Silvestri, A.; Spadoni, I.; Sorribas, M.; Wiest, R.; Mileti, E.; Galbiati, M.; Invernizzi, P.; Adorini, L. Microbiota-driven gut vascular barrier disruption is a prerequisite for non-alcoholic steatohepatitis development. J. Hepatol. 2019, 71, 1216–1228. [Google Scholar]
  127. Albillos, A.; de Gottardi, A.; Rescigno, M. The gut-liver axis in liver disease: Pathophysiological basis for therapy. J. Hepatol. 2020, 72, 558–577. [Google Scholar]
  128. Chen, M.; Hui, S.; Lang, H.; Zhou, M.; Zhang, Y.; Kang, C.; Zeng, X.; Zhang, Q.; Yi, L.; Mi, M. SIRT3 Deficiency Promotes High-Fat Diet-Induced Nonalcoholic Fatty Liver Disease in Correlation with Impaired Intestinal Permeability through Gut Microbial Dysbiosis. Mol. Nutr. Food Res. 2019, 63, e1800612. [Google Scholar]
  129. Thin, L.W.Y.; Lawrance, I.C.; Spilsbury, K.; Kava, J.; Olynyk, J.K. Detection of liver injury in IBD using transient elastography. J. Crohn’s Colitis 2014, 8, 671–677. [Google Scholar] [CrossRef]
  130. Carr, R.M.; Patel, A.; Bownik, H.; Oranu, A.; Kerner, C.; Praestgaard, A.; Forde, K.A.; Reddy, K.R.; Lichtenstein, G.R. Intestinal Inflammation Does Not Predict Nonalcoholic Fatty Liver Disease Severity in Inflammatory Bowel Disease Patients. Dig. Dis. Sci. 2017, 62, 1354–1361. [Google Scholar] [CrossRef]
  131. Bessissow, T.; Le, N.H.; Rollet, K.; Afif, W.; Bitton, A.; Sebastiani, G. Incidence and Predictors of Nonalcoholic Fatty Liver Disease by Serum Biomarkers in Patients with Inflammatory Bowel Disease. Inflamm. Bowel Dis. 2016, 22, 1937–1944. [Google Scholar] [CrossRef] [PubMed]
  132. Shen, B.; Gu, T.; Shen, Z.; Zhou, C.; Guo, Y.; Wang, J.; Li, B.; Xu, X.; Li, F.; Zhang, Q. Escherichia coli Promotes Endothelial to Mesenchymal Transformation of Liver Sinusoidal Endothelial Cells and Exacerbates Nonalcoholic Fatty Liver Disease Via Its Flagellin. Cell Mol. Gastroenterol. Hepatol. 2023, 16, 857–879. [Google Scholar] [PubMed]
  133. Han, Y.; Glueck, B.; Shapiro, D.; Miller, A.; Roychowdhury, S.; Cresci, G.A.M. Dietary Synbiotic Supplementation Protects Barrier Integrity of Hepatocytes and Liver Sinusoidal Endothelium in a Mouse Model of Chronic-Binge Ethanol Exposure. Nutrients 2020, 12, 373. [Google Scholar] [CrossRef]
  134. Yao, Z.; Mates, J.M.; Cheplowitz, A.M.; Hammer, L.P.; Maiseyeu, A.; Phillips, G.S.; Wewers, M.D.; Rajaram, M.V.; Robinson, J.M.; Anderson, C.L. Blood-Borne Lipopolysaccharide Is Rapidly Eliminated by Liver Sinusoidal Endothelial Cells via High-Density Lipoprotein. J. Immunol. 2016, 197, 2390–9239. [Google Scholar] [CrossRef]
  135. Zheng, Y.; Wang, J.; Wang, J.; Xie, H.; Zhao, T. Effect of Curcumol on the Fenestrae of Liver Sinusoidal Endothelial Cells Based on NF-κB Signaling Pathway. Evid. Based Complement Altern. Med. 2020, 2020, 8590638. [Google Scholar] [CrossRef]
  136. Cheluvappa, R.; Denning, G.M.; Lau, G.W.; Grimm, M.C.; Hilmer, S.N.; Le Couteur, D.G. Pathogenesis of the hyperlipidemia of Gram-negative bacterial sepsis may involve pathomorphological changes in liver sinusoidal endothelial cells. Int. J. Infect. Dis. 2010, 14, e857–e867. [Google Scholar] [CrossRef]
  137. Sarphie, T.G.; D’Souza, N.B.; Deaciuc, I.V. Kupffer cell inactivation prevents lipopolysaccharide-induced structural changes in the rat liver sinusoid: An electron-microscopic study. Hepatology 1996, 23, 788–796. [Google Scholar] [CrossRef]
  138. Uhrig, A.; Banafsche, R.; Kremer, M.; Hegenbarth, S.; Hamann, A.; Neurath, M.; Gerken, G.; Limmer, A.; Knolle, P.A. Development and functional consequences of LPS tolerance in sinusoidal endothelial cells of the liver. J. Leukoc. Biol. 2005, 77, 626–633. [Google Scholar] [CrossRef]
  139. Gaitantzi, J.; Karch, L.; Germann, C.; Cai, V.; Rausch, E.; Birgin, N.; Rahbari, T.; Seitz, C.; Hellerbrand, C.; König, H.G.; et al. Breitkopf-Heinlein, BMP-9 Modulates the Hepatic Responses to LPS. Cells 2020, 9, 617. [Google Scholar] [CrossRef]
  140. Meijnikman, A.S.; Davids, M.; Herrema, H.; Aydin, O.; Tremaroli, V.; Rios-Morales, M.; Levels, H.; Bruin, S.; de Brauw, M.; Verheij, J.; et al. Nieuwdorp, Microbiome-derived ethanol in nonalcoholic fatty liver disease. Nat. Med. 2022, 28, 2100–2106. [Google Scholar]
  141. Wang, B.Y.; Ju, X.H.; Fu, B.Y.; Zhang, J.; Cao, Y.X. Effects of ethanol on liver sinusoidal endothelial cells-fenestrae of rats. Hepatobiliary Pancreat. Dis. Int. HBPD INT 2005, 4, 422–426. [Google Scholar] [PubMed]
  142. Scanlan, P.D. Bacteria-Bacteriophage Coevolution in the Human Gut: Implications for Microbial Diversity and Functionality. Trends Microbiol. 2017, 25, 614–623. [Google Scholar] [CrossRef] [PubMed]
  143. Øie, C.I.; Wolfson, D.L.; Yasunori, T.; Dumitriu, G.; Sørensen, K.K.; McCourt, P.A.; Ahluwalia, B.S.; Smedsrød, B. Liver sinusoidal endothelial cells contribute to the uptake and degradation of entero bacterial viruses. Sci. Rep. 2020, 10, 898. [Google Scholar] [CrossRef]
  144. Yang, H.; Wang, T.; Qian, C.; Wang, H.; Yu, D.; Shi, M.; Fu, M.; Liu, X.; Pan, M.; Rong, X.; et al. Gut microbial-derived phenylacetylglutamine accelerates host cellular senescence. Nat. Aging 2025, 5, 401–418. [Google Scholar] [CrossRef]
  145. Han, Y.; Ling, Q.; Wu, L.; Wang, X.; Wang, Z.; Chen, J.; Zheng, Z.; Zhou, Z.; Jia, L.; Li, L.; et al. Akkermansia muciniphila inhibits nonalcoholic steatohepatitis by orchestrating TLR2-activated γδT17 cell and macrophage polarization. Gut. Microbes 2023, 15, 2221485. [Google Scholar] [CrossRef]
  146. Song, Q.; Zhang, X.; Liu, W.; Wei, H.; Liang, W.; Zhou, Y.; Ding, Y.; Ji, F.; Cheung, A.H.-K.; Wong, N.; et al. Bifidobacterium pseudolongum-generated acetate suppresses non-alcoholic fatty liver disease-associated hepatocellular carcinoma. J. Hepatol. 2023, 79, 1352–1365. [Google Scholar] [CrossRef]
  147. de Oca, A.P.-M.; Julián, M.T.; Ramos, A.; Puig-Domingo, M.; Alonso, N. Microbiota, Fiber, and NAFLD: Is There Any Connection? Nutrients 2020, 12, 3100. [Google Scholar] [CrossRef]
  148. Reshef, N.; Gophna, U.; Reshef, L.; Konikoff, F.; Gabay, G.; Zornitzki, T.; Knobler, H.; Maor, Y. Prebiotic Treatment in Patients with Nonalcoholic Fatty Liver Disease (NAFLD)—A Randomized Pilot Trial. Nutrients 2024, 16, 1571. [Google Scholar] [CrossRef]
  149. Parnell, J.A.; Raman, M.; Rioux, K.P.; Reimer, R.A. The potential role of prebiotic fibre for treatment and management of non-alcoholic fatty liver disease and associated obesity and insulin resistance. Liver Int. Off. J. Int. Assoc. Study Liver 2012, 32, 701–711. [Google Scholar] [CrossRef]
Lipidology 02 00010 g001
Figure 1. Role of functional LSECs in normal individuals and capillarized LSECs in metabolic dysfunction-associated steatotic liver disease (MASLD). The pathogenesis of MASLD is driven by diet, lifestyle, genetic risk, and environmental challenges, in which the gut–liver plays a pivotal role. In the gut–liver axis, liver sinusoidal endothelial cells (LSECs) form the barrier between hepatocytes and portal blood enriched with gut-derived molecules. In a healthy physiological situation, LSECs play an essential role to maintain the homeostasis of liver since they (1) produce nitric oxide (NO) for vasodilation in response to shear stress from blood flow, (2) have fenestrae and lack a basement membrane ensuring substance exchange between the space of Disse and the circulation, (3) express multiple scavenger receptors enabling them to clear numerous metabolic products from sinusoidal blood, and (4) keep hepatic stellate cells (HSCs) and Kupffer cells (KCs) quiescent and thus prevent or inhibit collagen production and inflammatory activation. Hepatocytes maintain LSEC fenestration paracrine factors such as vascular endothelial growth factor A (VEGFA) and bone morphogenetic protein 9 (BMP9). Capillarized LSECs contribute to MASLD-progression since they (1) have a reduced NO production, (2) have an injured vascular barrier integrity due to the absence of fenestrae and the presence of a basement membrane, (3) display an impaired clearance and scavenger capacity, and (4) activate HSCs and KCs.
Figure 1. Role of functional LSECs in normal individuals and capillarized LSECs in metabolic dysfunction-associated steatotic liver disease (MASLD). The pathogenesis of MASLD is driven by diet, lifestyle, genetic risk, and environmental challenges, in which the gut–liver plays a pivotal role. In the gut–liver axis, liver sinusoidal endothelial cells (LSECs) form the barrier between hepatocytes and portal blood enriched with gut-derived molecules. In a healthy physiological situation, LSECs play an essential role to maintain the homeostasis of liver since they (1) produce nitric oxide (NO) for vasodilation in response to shear stress from blood flow, (2) have fenestrae and lack a basement membrane ensuring substance exchange between the space of Disse and the circulation, (3) express multiple scavenger receptors enabling them to clear numerous metabolic products from sinusoidal blood, and (4) keep hepatic stellate cells (HSCs) and Kupffer cells (KCs) quiescent and thus prevent or inhibit collagen production and inflammatory activation. Hepatocytes maintain LSEC fenestration paracrine factors such as vascular endothelial growth factor A (VEGFA) and bone morphogenetic protein 9 (BMP9). Capillarized LSECs contribute to MASLD-progression since they (1) have a reduced NO production, (2) have an injured vascular barrier integrity due to the absence of fenestrae and the presence of a basement membrane, (3) display an impaired clearance and scavenger capacity, and (4) activate HSCs and KCs.
Lipidology 02 00010 g001
Table 1. Scavenger receptors and their ligands on LSECs.
Table 1. Scavenger receptors and their ligands on LSECs.
Scavenger ReceptorLigands
SR-A/MSR1/SCARA1/CD204Ox-LDL/Ac-LDL/β-amyloid fibrils
AGEs/LPS/LTA/MDAASB
Dextran sulfate/Polyinosinic acid
Fucoidan
SR-B1/SCARB1LDL/VLDL/HDL
Lipophilic vitamins/Carotenoids
Silica/HCV/ApoA1/ApoE
SR-B2/CD36HDL/LDL/VLDL/LCFA/Ox-LDL
Apoptotic bodies/Collagen
Aldehyde-modified proteins
TSP-1/AGEs
SR-E3/MRC1/CD206Lysosomal enzymes/tPA/PICP
Types I–IV Collagen
High-mannose oligosaccharides
Mannosylated glycoproteins
Mycobacterial lipoarabinomannan
Yeast mannans (Candida albicans)
SR-H1/Stabilin 1HA/Chondroitin sulfate/Ox-LDL
Ac-LDL/AGEs/Heparin/LPS
PAO/Placental lactogen
Growth hormones
SR-H2/Stabilin 2Heparin/Collagen/Chondroitin sulfate
Ox-LDL/Ac-LDL/AGEs/LPS
Phosphatidylserine/Growth hormones
SR-J/RAGEAGEs/S100 Proteins
HMGB1/Aβ/LPA/IAPP
Complement protein C1q
SR-K1/CD44HA/Glycoproteins/OPN
Collagen/Fibronectin
SR-L/CD91/LRP1/A2MRApoE/tPA/A2M
Receptor-associated protein
Lactoferrin/CTGF
Factor VIII/HSP/Aβ
Protease-Inhibitor Complexes
Table 2. Changes in scavenger receptors in LSECs in MASLD.
Table 2. Changes in scavenger receptors in LSECs in MASLD.
Scavenger ReceptorChanges in MASLD
SR-A/MSR1/SCARA1/CD204Increased
SR-B1/SCARB1Increased/no change
SR-B2/CD36Increased
SR-E3/MRC1/CD206Reduced/no change
SR-H1/Stabilin 1Unknown
SR-H2/Stabilin 2Unknown
SR-J/RAGEIncreased
SR-K1/CD44Increased
SR-L/CD91/LRP1/A2MRReduced
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Chen, T.; Grefhorst, A.; Holleboom, A.G. Liver Sinusoidal Endothelium: The Hidden Interface in the Gut–Liver Axis in Metabolic Dysfunction-Associated Steatotic Liver Disease? Lipidology 2025, 2, 10. https://doi.org/10.3390/lipidology2020010

AMA Style

Chen T, Grefhorst A, Holleboom AG. Liver Sinusoidal Endothelium: The Hidden Interface in the Gut–Liver Axis in Metabolic Dysfunction-Associated Steatotic Liver Disease? Lipidology. 2025; 2(2):10. https://doi.org/10.3390/lipidology2020010

Chicago/Turabian Style

Chen, Ting, Aldo Grefhorst, and Adriaan G. Holleboom. 2025. "Liver Sinusoidal Endothelium: The Hidden Interface in the Gut–Liver Axis in Metabolic Dysfunction-Associated Steatotic Liver Disease?" Lipidology 2, no. 2: 10. https://doi.org/10.3390/lipidology2020010

APA Style

Chen, T., Grefhorst, A., & Holleboom, A. G. (2025). Liver Sinusoidal Endothelium: The Hidden Interface in the Gut–Liver Axis in Metabolic Dysfunction-Associated Steatotic Liver Disease? Lipidology, 2(2), 10. https://doi.org/10.3390/lipidology2020010

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