Search Results (150)

Metabolic dysfunction-associated fatty liver disease (MAFLD), a recently proposed term to replace non-alcoholic fatty liver disease (NAFLD), emphasizes the critical role of metabolic dysfunction and applies broader diagnostic criteria. Diagnosis of MAFLD requires evidence of hepatic steatosis combined with obesity, type 2 diabetes mellitus, or other metabolic dysregulation conditions, all of which significantly elevate the risk of chronic kidney disease (CKD). This review discusses the pathological mechanisms of lipid accumulation and insulin resistance in MAFLD and CKD, highlighting their mechanistic connections. Specifically, ectopic fat accumulation triggered by metabolic reprogramming, oxidative stress and inflammation induced by energy overload, modified lipids, uremic toxins, and senescence, as well as insulin resistance pathways activated by pro-inflammatory factors and lipotoxic products, collectively exacerbate simultaneous hepatic and renal injury. Moreover, interactions among hyperinsulinemia, the sympathetic nervous system, the renin–angiotensin system (RAS), and altered adipokine and hepatokine profiles further amplify insulin resistance, ectopic lipid deposition, and systemic damage. Finally, the review explores potential therapeutic strategies targeting lipid metabolism, insulin sensitivity, and RAS activity, which offer promise for dual-organ protection and improved outcomes in both hepatic and renal systems. Full article

Background/Objectives: Metabolic dysfunction-associated fatty liver disease (MAFLD) is a chronic hepatic condition marked by lipid buildup, lipotoxicity, and inflammation. Prior research indicates that 3,3′-Diindolemethane (DIM), a natural indole-type phytochemical that is abundant in brassicaceae vegetables, has been reported to reduce body weight and improve lipid metabolism in mice subjected to a high-fat diet (HFD). The aryl hydrocarbon receptor (AhR), a nuclear receptor implicated in lipid metabolism and immune regulation, serves as a functional receptor for DIM. However, the underlying signaling pathways that regulate MAFLD remain elusive. Our objective is to ascertain the beneficial impact of DIM on MAFLD and the associated mechanisms. Methods: Hematoxylin and eosin staining, together with Oil Red O staining, were utilized to assess the pathological changes and lipid deposition in the liver. Biochemical analysis was employed to measure levels of triglyceride (TG), total cholesterol (TC), free fatty acid (FFA), aspartate transaminase (AST), alanine transaminase (ALT), low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C). The cell survival rate of HepG2 cells treated with palmitic acid (PA) and DIM was assessed using the CCK-8 assay. Flow cytometry was employed to measure the fluorescence intensity emitted by lipid droplets within cells. Western blotting analysis was performed to assess AhR pathway and fatty acid transporter expression levels in hepatic tissue. Results: Our results showed that DIM significantly attenuated body weight gain and hepatic injury brought on by HFD, decreased lipid droplet accumulation in HepG2 cells, and effectively suppressed the phosphorylation of p38 MAPK and the protein expression levels of fatty acid transporters CD36 and FATP4. Conclusions: DIM reduced lipid accumulation by activating AhR and suppressing p38 MAPK phosphorylation, thereby inhibiting fatty acid transport and inflammatory responses. These findings suggest that DIM may represent a promising therapeutic candidate for MAFLD, warranting further exploration for clinical applications. Full article

Background: Early-life stress and dietary habits are key determinants of metabolic health. This study investigates the combined effects of maternal separation (MS) and a post-weaning high-fat diet (HFD) on liver morphology in male C57BL/6 mice. Methods: Male mice were subjected to MS during early postnatal life or kept unmanipulated (UM). After weaning, animals were assigned to either a control diet (CD) or an HFD, forming four groups: UM-CD, UM-HFD, MS-CD, and MS-HFD. Liver histology, collagen deposition, and both morphometric and stereological parameters were assessed following 16 weeks of dietary intervention. Results: MS and HFD independently altered liver structure, while the combination of both factors intensified these changes. The MS-HFD group exhibited pronounced steatosis, mixed inflammatory infiltrates, and hepatocellular ballooning, with a significantly higher NAFLD Activity Score (NAS). No significant differences were observed in liver fibrosis. Morphometric analysis revealed increased body mass in HFD-fed groups and elevated liver mass in MS-HFD. Liver volume was higher in MS-HFD, though not significantly. Liver stereology revealed reduced numerical density of hepatocytes (Nv_hep) and increased surface density (Sv_hep) in MS groups, with the most pronounced effects in MS-HFD. Conclusions: Maternal separation amplifies the hepatic alterations induced by HFD, promoting early inflammatory and steatotic changes. These findings highlight the significance of early-life stress as a factor increasing susceptibility to diet-induced liver damage. Full article

Background: This study aims to investigate the impact of coal dust (silicon dioxide) exposure on dyslipidemia and its underlying mechanisms, with a focus on the association between coal dust exposure and hepatic metabolic disorders. Methods: Clinical data were collected from 5433 coal mine workers to compare the incidence of dyslipidemia between the dust-exposed group and the non-exposed group. A mouse model of silicon dioxide exposure was established to observe hepatic fat accumulation and pathological changes. Liver tissue sequencing was performed to screen for key differential genes. In vitro cell experiments were utilized to identify the molecular mechanisms underlying hepatocyte metabolic abnormalities induced by silicon dioxide exposure. Results: Clinical data revealed that 69.2% of miners in the dust-exposed group developed dyslipidemia, which was higher than the 30.7% in the non-exposed group. Animal data showed that silicon dioxide exposure led to hepatic fat deposition and pathological damage, with the degree of injury positively correlated with exposure time. Liver sequencing identified a significant upregulation of the FMO3 (flavin monooxygenase 3) gene in mouse liver tissue following silicon dioxide exposure, accompanied by enhanced inflammatory responses. Mechanistic studies demonstrated that silicon dioxide activates Kupffer cells to secrete IL-6 (interleukin-6), which induces high expression of FMO3 in hepatocytes through the PKC/YY1 signaling pathway, thereby disrupting lipid metabolism. Conclusions: Silicon dioxide exposure can promote the upregulation of FMO3 expression in hepatocytes by activating Kupffer cells to release IL-6 via the PKC/YY1 pathway, ultimately leading to lipid metabolic disorders and dyslipidemia Full article

This study investigated whether the supplementation of prebiotic inulin to gestating sows programmatically affects offspring growth performance and meat quality while exploring its epigenetic effects through histone acetylation modulation. After mating, sixty multiparous sows (Landrace × Yorkshire; parity 2–3) were assigned to a 2 × 2 factorial arrangement with inulin (0% vs. 1.5%) and fat (0% or 5%) supplementation until farrowing. Post-weaning, five litters (10 piglets per litter) per treatment were selected and maintained in their original litter for fattening under standardized feeding. The results demonstrated that maternal inulin supplementation during gestation accomplished the following: (1) Increased offspring liver index by 13.4% at weaning and 6.8% at finishing (p < 0.05) while reducing the finishing-phase backfat thickness by 11.6% (p < 0.01), with a significant inulin × fat interaction attenuating fat-induced abdominal lipid accumulation at weaning (p = 0.05). (2) Decreased longissimus dorsi muscle lightness (L*) by 4.5% in finishing pigs (p = 0.02) without altering the other meat quality parameters. (3) Suppressed offspring liver lipid deposition at birth and finishing (p < 0.05), concomitant with upregulated hepatic PGC-1α and CPT1A expression (p < 0.05). (4) Elevated neonatal serum butyrate by 15.6% (p = 0.06) while inhibiting hepatic histone deacetylase (HDAC) activity and enhancing histone H3/H4 acetylation (p < 0.01). These findings suggest that maternal inulin supplementation during gestation mitigates offspring hepatic lipid deposition through butyrate-mediated epigenetic regulation, where microbial-derived butyrate from inulin fermentation inhibits HDAC activity, enhances histone acetylation levels, and upregulates fatty acid β-oxidation gene expression. This study provides novel mechanistic insights into how maternal dietary fiber nutrition programs offspring development through epigenetic reprogramming. Full article

Background: Estrogen plays a crucial role in adipose tissue homeostasis, influencing fat distribution, lipid metabolism, and insulin sensitivity. Through estrogen receptor (ER) activation, particularly ERα, estradiol (E2) regulates adipogenesis, inhibits adipocyte hypertrophy, and promotes insulin signaling. It enhances lipid oxidation, reduces lipogenesis, and suppresses pro-inflammatory cytokine production, thereby maintaining metabolic health. Primary ovarian insufficiency (POI), characterized by estrogen deficiency before the age of 40, disrupts this regulatory network, leading to adverse metabolic effects. Objetives: This review examines the effects of estrogen on adipose tissue, lipid metabolism, and carbohydrate metabolism, with a particular focus on clinical evidence in women with POI. Methods: A narrative review of the metabolic alterations associated with POI, emphasizing the molecular, biochemical, and metabolic mechanisms underlying estrogen deficiency, with a special focus on adipose tissue. Results: Women with POI exhibit increased visceral fat accumulation, reduced lean mass, and alterations in adipokine secretion, resembling the metabolic phenotype of postmenopausal women. The decline in estrogen levels contributes to central adiposity, impaired lipid metabolism, and insulin resistance, exacerbating the risk of type 2 diabetes (T2D) and cardiovascular disease (CVD). The loss of estrogenic regulation leads to enhanced lipolysis in visceral fat, raising free fatty acid flux to the liver, promoting hepatic steatosis, and worsening insulin resistance. Studies indicate that POI patients have significantly higher total cholesterol, low-density lipoprotein (LDL) cholesterol, and triglycerides compared to age-matched controls, reinforcing their heightened CVD risk. Reduced sex hormone-binding globulin (SHBG) levels increase free androgen availability, aggravating central fat deposition. These metabolic disturbances can potentially accelerate atherosclerosis and vascular aging, increasing morbidity and mortality in POI patients. Conclusions: Understanding the role of estrogen in adipose tissue and its disruption in POI highlights the importance of early intervention. Although the available evidence is limited and largely extrapolated from menopause studies, strategies such as hormone replacement therapy, lifestyle modifications, and lipid profile optimization are essential to mitigate metabolic consequences and improve long-term health outcomes in women with POI. Full article

Maintaining the normal biological rhythms of livestock is of great significance for reflecting the environmental suitability and welfare level of animals. Mistimed feeding can interfere with the circadian rhythms of both humans and animals, resulting in disorders of lipid metabolism, obesity, and metabolic syndrome. Low-temperature environment stimulates increased appetite and decreased physical activity, resulting in higher energy intake than consumption and thus facilitating fat deposition and even obesity. In this study, growing rabbits were randomly allocated to the daytime feeding (DF) group and nighttime restricted feeding (NRF) group. Our research demonstrated that, during winter, the DF regimen disrupted the behavioral rhythms of rabbits and accelerated weight gain without changing overall feed intake. The underlying reason was that DF disturbed the lipid metabolism rhythms, promoted hepatic lipid synthesis regulated by DGAT1 and lipid synthesis of adipose tissues regulated by GPAM, thus triggering fat deposition. In contrast, the NRF regimen enhanced thermogenesis regulated by T3 and elevated body temperature and facilitated ketogenesis mediated by HMGCS2, increasing energy consumption. However, it had no significant impact on the fat content within muscle. This study offers a theoretical foundation for the refinement of feeding management and healthy raising of rabbits. Full article

(1) Background: Hepatic lipid accumulation is the initial factor in metabolic-associated fatty liver disease (MAFLD) in type 2 diabetics, leading to accelerated liver damage. The NOD-like receptor protein 3 (NLRP3) inflammasome plays a critical role in this process. Dapansutrile (DAPA) is a novel NLRP3 inflammasome inhibitor; however, its effect on ectopic lipid accumulation in the liver remains unclear. This study aimed to investigate the therapeutic effect of DAPA on hepatic lipid accumulation in a diabetic mouse model and its potential mechanisms. (2) Methods: The effects of DAPA on hepatic ectopic lipid deposition and liver function under metabolic stress were evaluated in vivo using db/db and high-fat diet (HFD) + streptozotocin (STZ) mouse models. Additionally, the role and mechanism of DAPA in cellular lipid deposition, mitochondrial oxidative stress, and inflammation were assessed in HepG2 cells treated with free fatty acids (FFA) and DAPA. (3) Results: Our findings indicated that DAPA treatment improved glucose and lipid metabolism in diabetic mice, particularly addressing liver heterotopic lipid deposition and insulin resistance. DAPA treatment also ameliorated lipid accumulation and mitochondrial-related functions and inflammation in HepG2 cells through the NLRP3-Caspase-1 signaling axis. (4) Conclusions: Targeting NLRP3 with DAPA may represent a novel therapeutic approach for diabetes-related fatty liver diseases. Full article

Introduction: Metabolic dysfunction-associated steatohepatitis (MASH) is a leading cause of liver failure globally and is characterized by hepatic steatosis and inflammation, which may progress to fibrosis, the severity of which is highly predictive of patient demise and death. In view of the lack of treatment options for MASH, we investigated the therapeutic properties of extracellular vesicles (EVs) from normal human hepatocytes, which we have previously been shown to alleviate toxin-mediated hepatic fibrosis in mice. Methods: C57BI/6J mice were fed a choline-deficient amino acid-defined high (60%) fat (CDAA-HF) diet for up to 12 weeks while receiving i.p. administration of EVs purified from cultured human HepG2 hepatocytes. Results: CDAA-HF diet consumption resulted in severe hepatic steatosis, increased frequency of CD45+ lymphocytes and F4/80+ macrophages, robust production of aortic smooth muscle actin (ACTA2), and deposition of interstitial collagen, as well as altered serum levels of ALT, AST, cholesterol, triglycerides, alkaline phosphatase, unconjugated bilirubin, and total protein, thus recapitulating typical MASH phenotypes. EVs administered preventively or therapeutically resulted in the restoration of serum marker levels, reduced hepatic inflammation and attenuation of collagen deposition, ACTA2 production, and expression of fibrosis-associated genes. HepG2 EVs contained 205 miRs and, among the 30 most abundant miRs, seven (miRs-423-5p, -483-5p, -191-5p, -148a-3p, -423-3p, -92a-3p, -122-5p) are predicted to directly target fibrosis-related genes (collagens, ACTA2, MMPs, and TIMPs). Conclusions: Hepatocyte EVs are therapeutic in a mouse model of diet-induced steatohepatitis with fibrosis. Further studies of hepatocyte EVs or their cargo components as novel therapeutics for MASH in humans are warranted, including treatment of fibrotic stages, which are associated with clinical demise and are predictive of patient death. Full article

Multiply adverse effects including declines in production performance and excessive fat deposition were noticed with the extension of the laying cycle in hens, which are pertinent to animal welfare and human food safety. This study aimed to investigate the effect of dietary supplementation of bile acids (BAs) on production performance and lipid metabolism in late-phase laying hens. A total of 144 70-week-old hens were distributed into three treatments with eight replicates per treatment, including the basal diet with 0 (Ctrl), 95.01 (Low-BA), and 189.99 mg/kg (High-BA) of porcine BAs, respectively. The test period was from 70 to 75 weeks. The supplementation of BAs did not significantly alter laying performance during the trial, whereas it increased (p < 0.05) the total follicles compared to the Ctrl diet. The eggs from the hens fed the BA diet exhibited increased (p > 0.05) relative weight of eggshell and yolk color than those that consumed the Ctrl diet. There were no significant changes following BA treatment regarding the serum lipid profile. Dietary BA treatment reduced the total triglyceride in livers to different extents, resulting in the decreased diameter and area of vacuoles in liver tissues. The low-dose BA treatment decreased the mRNA levels of fatty acid synthase (FASN) and stearoyl-CoA desaturase (SCD), while promoting the expression of lipoprotein lipase (LPL) compared to the Ctrl group (both p < 0.05). Of note, the expressions of farnesoid X receptor (FXR), apical sodium-dependent bile acid transporter (ASBT), and ileum bile acid-binding protein (IBABP) were notably downregulated (p < 0.05) by the low-dose BA treatment. Dietary BA treatment had no apparent effects on laying performance, whereas it increased the follicle frequency, eggshell weight, and yolk color. Moreover, a diet containing 95.01 mg/kg of BAs depressed ileal BA resorption and hepatic fatty deposition by reducing lipogenesis and promoting lipolysis, which may have a beneficial effect on the liver in late-phase layers. Full article

Consuming a “modern” Western diet and overnutrition may increase insulin secretion. Additionally, nutrition-mediated hyperinsulinemia is a major driver of ectopic fat deposition. The global prevalence of metabolic syndrome is high and growing. Within this context, people with congenital lipodystrophy often experience a severe form of metabolic syndrome. Evidence is increasingly supporting that subtle partial lipodystrophy plays an important role in the development of metabolic syndrome in the general population. In individuals in the general population with subtle partial lipodystrophy, as well as in those with congenital lipodystrophy, the subcutaneous adipose tissues are unable to accommodate surplus energy intake. In both conditions, (excess) fat is directed toward the liver, pancreas, and muscles, where it is deposited as ectopic fat, as this fat can no longer be stored in the “safe” subcutaneous fat depots. Ectopic fat depositions cause insulin resistance in the liver and muscles, as well as β-cell dysfunction in the pancreas. Support of a direct pathological role of ectopic fat deposition in this condition is further provided by the rapid normalization of hepatic insulin sensitivity and improvement in pancreatic β-cell function after marked reductions in ectopic fat depositions. Thus, ectopic fat deposition in the liver, pancreas, and muscles may play a causal role in the pathogenesis of metabolic syndrome even in the general population. As such, the prevention of ectopic fat deposition may reduce the risk of metabolic syndrome and mitigate its effects. Full article

Metabolic dysfunction-associated steatotic liver disease (MASLD) represents a refined categorization of non-alcoholic fatty liver disease (NAFLD), highlighting the intricate relationship between hepatic steatosis and metabolic dysfunction. Abdominal obesity (AO), a key diagnostic criterion for metabolic dysfunction, predominantly results from inappropriate diet and unhealthy dietary habits. To comprehensively investigate which dietary factors contribute to MASLD through AO and to understand the underlying biological mechanisms, we initially conducted a systematic review of meta-analysis articles in the PubMed database from the past decade, summarizing dietary factors that affect AO. Subsequently, we conducted targeted searches in the PubMed database for these dietary factors and provided a narrative review of the mechanisms of how these dietary factors lead to AO and how AO exacerbates MASLD. A diet characterized by excessive intake of energy, carbohydrates, fructose, or ultra-processed foods (UPFs) is considered inappropriate. Inappropriate diet leads to the formation of MASLD and AO by enhancing pathways such as de novo lipid synthesis (DNL) in the liver, insulin resistance (IR), gut–liver dysfunction, and inflammation. Dietary interventions for inappropriate diets can effectively intervene in and improve MASLD and AO. The mechanism of inappropriate diet on abdominal fat deposition is through excessive energy or the activation of the enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD-1) to increase endocortisol secretion. Then, the excessive accumulation of visceral fat facilitates a rapid and augmented flux of free fatty acids (FFAs) to the liver and initiates a series of deleterious effects, including oxidative stress (OS), endoplasmic reticulum stress (ERS), activation of protein kinase C (PKC) pathways, and inflammation. Additionally, FFAs may mediate excessive lipid deposition and hepatocellular damage through the action of hormones. These pathways to liver damage exacerbate MASLD and progression to metabolic dysfunction-associated steatohepatitis (MASH) and fibrosis. Furthermore, investigating other potential mechanisms by which AO may influence MASLD could offer new recommendations for the treatment guidelines of MASLD. Full article

The aim of this study was to evaluate the potential effects of administering mangaba powder on liver function and somatic, oxidative and lipid metabolism parameters in rats fed a high-fat diet. Prepared mangaba powder has important amounts of phenolic compounds, vitamin C, dietary fiber and oligosaccharides. A total of 32 adult Wistar rats were initially randomized into two groups for the biological assay: normal-fat (NF, n = 16) and high-fat (HF, n = 16) diets for 21 days. These rats were subsequently subdivided into four groups: NF (n = 8), HF (n = 8), normal-fat diet with mangaba powder administration (NFMG, n = 8) and high-fat diet with mangaba powder administration (HFMG, n = 8). The treatment with mangaba powder (400 mg/kg) lasted an additional 28 days. Compared to the HF rats, the HFMG rats showed an 8% reduction in the body mass index. Treatment with mangaba reduced the serum cholesterol by 18%, as well as the hepatic deposition of triacylglycerides by 26% and cholesterol by 25%, in addition to increasing bile acid synthesis by 77% in this organ. Mangaba powder consumption attenuated the degree of hepatic steatosis, reduced lipid peroxidation and increased the serum and hepatic antioxidant capacity in HFMG rats. These results show that the consumption of mangaba powder had lipid-lowering, hepatoprotective and antioxidant effects, especially in HFMG rats, which may be associated with an additive and synergistic action between the bioactive compounds present in the product. Full article

The inhibitor-kappaB kinase epsilon (IKKε) represents a non-canonical IκB kinase that modulates NF-κB activity and interferon I responses. Inhibition of this pathway has been linked with atherosclerosis and metabolic dysfunction-associated steatotic liver disease (MASLD), yet the results are contradictory. In this study, we employed a combined model of hepatic PCSK9^D377Y overexpression and a high-fat diet for 16 weeks to induce atherosclerosis and liver steatosis. The development of atherosclerotic plaques, serum lipid concentrations, and lipid metabolism in the liver and adipose tissue were compared between wild-type and IKKε knock-out mice. The formation and progression of plaques were markedly reduced in IKKε knockout mice, accompanied by reduced serum cholesterol levels, fat deposition, and macrophage infiltration within the plaque. Additionally, the development of a fatty liver was diminished in these mice, which may be attributed to decreased levels of multiple lipid species, particularly monounsaturated fatty acids, triglycerides, and ceramides in the serum. The modulation of several proteins within the liver and adipose tissue suggests that de novo lipogenesis and the inflammatory response are suppressed as a consequence of IKKε inhibition. In conclusion, our data suggest that the knockout of IKKε is involved in mechanisms of both atherosclerosis and MASLD. Inhibition of this pathway may therefore represent a novel approach to the treatment of cardiovascular and metabolic diseases. Full article

Non-alcoholic fatty liver disease (NAFLD) is a severe hepatic health threat with no effective treatment. Based on the results that Chenopodium quinoa Willd. flavonoids eluted with 30% ethanol (CQWF30) can effectively alleviate NAFLD, this study employed ultrahigh-performance liquid chromatography–electrospray ionization–tandem mass spectrometry (UPLC-ESI-MS/MS) to analyze the components of CQWF30., and screened for flavonoids with potential NAFLD-mitigating effects through network pharmacology. In vitro models using HepG2 and BEL-7402 cell lines induced with free fatty acid (FFA) showed that isorhamnetin administration reduced intracellular lipid deposition and reversed elevated triglyceride (TG) and total cholesterol (T-CHO) levels. In vivo experiments in high-fat diet (HFD) mice demonstrated that isorhamnetin significantly lowered serum and liver fat content, mitigated liver damage, and modulated bile acid metabolism by upregulating FXR and BSEP and downregulating SLCO1B3. Consequently, isorhamnetin shows promise as a treatment for NAFLD due to its lipid-lowering and hepatoprotective activities. Full article