Search Results (997)

Background: Apolipoprotein A-IV (ApoA-IV) is involved in lipid metabolism and energy homeostasis, but its role in hepatic adaptation to dietary stress remains incompletely understood. This study aimed to determine whether ApoA-IV deficiency alters hepatic transcriptional responses to high-fat diet (HFD) and to examine how these molecular changes relate to biochemical and histological features of liver function. Methods: Male ApoA-IV knockout (KO) and wild-type (WT) mice were fed either a normal diet (ND) or HFD for 12 weeks. Liver tissues were subjected to whole-transcriptome RNA sequencing, followed by differential expression and functional enrichment analyses. Results: Histological examination revealed persistent lobular and portal inflammation accompanied by mild fibrosis in ApoA-IV-KO mice irrespective of diet, whereas steatosis and hepatocellular ballooning were absent in all groups. Both dietary intervention and genotype were associated with transcriptomic and biochemical alterations, although the identified changes were primarily evident at the level of specific genes and biological pathways. ApoA-IV deficiency was associated with a more limited set of diet-related transcriptomic changes, reflected by fewer differentially expressed genes and enriched functional categories compared to WT mice. Functional enrichment analyses identified alterations predominantly related to lipid and sterol metabolism, including the statin pathway, triglyceride metabolism, PPAR signaling and cytochrome P450-associated processes. Notably, the statin pathway was the only functional category consistently distinguishing ApoA-IV-deficient and WT mice regardless of diet. Additionally, HFD-fed ApoA-IV-KO mice exhibited elevated serum triglyceride, alanine aminotransferase and insulin levels, in contrast to WT mice. Conclusions: ApoA-IV deficiency was associated with the modulation of selected metabolic and inflammatory pathways involved in hepatic responses to dietary challenge. Cholesterol- and sterol-related pathways, including the statin pathway, represented the most consistent genotype-associated transcriptomic signature. Within the context of the present model, the findings suggest that ApoA-IV may contribute to hepatic responses during early stages of metabolic adaptation to dietary stress, although the biological significance of the observed transcriptomic differences requires further investigation. Full article

Obesity is a prevalent metabolic disorder characterized by excessive lipid accumulation. This study aimed to investigate the anti-obesity effects and underlying mechanisms of two triterpenoid saponin-rich extracts, designated disaccharide saponin-rich extract (DTS) and trisaccharide/tetrasaccharide saponin-rich extract (TTS), prepared from adzuki bean (Vigna angularis). In vitro, both DTS and TTS extracts significantly inhibited lipid accumulation in 3T3-L1 adipocytes without cytotoxicity, with TTS reducing lipid droplets to 21.45% of the model group at 200 μg/mL. In vivo, C57BL/6J mice were fed a high-fat–high-cholesterol diet (HFD) for 12 weeks and orally administrated with DTS or TTS (30, 60, or 120 mg/kg/day) via gavage; the results showed marked reductions in body weight gain (up to 20.37%), fat mass, liver coefficient, and serum levels of total cholesterol (TC), triglyceride (TG), Low-Density Lipoprotein Cholesterol (LDL-C), Alanine Aminotransferase (ALT), and Aspartate Aminotransferase (AST), while elevating high-density lipoprotein cholesterol (HDL-C) levels. Mechanistically, transcriptomics and Western blot analyses revealed that both extracts were associated with upregulation of the PPARα-ACOX1 axis, consistent with enhanced fatty acid β-oxidation, and downregulation of the PPARγ-FABP4 pathway, consistent with reduced adipogenesis, suggesting a dual shift toward lipid catabolism and away from lipid synthesis. Furthermore, 16S rRNA sequencing demonstrated that both saponin extracts reversed HFD-induced gut dysbiosis by restoring α-diversity and orchestrating distinct genus-level modulations, specifically suppressing obesity-associated pathobionts (Faecalibaculum and Ileibacterium) while concurrently enriching beneficial commensals (Bifidobacterium). Notably, TTS at 120 mg/kg reduced body weight gain to a greater extent than the positive control orlistat (p < 0.05, Tukey’s HSD), with comparable improvements in serum lipid profiles and liver function parameters. Collectively, these findings demonstrate that adzuki bean saponin extracts exert anti-obesity effects in HFD-fed mice and are associated with multi-target changes involving the “liver–adipose–gut axis,” supporting their further evaluation as candidate as functional food ingredients for metabolic health. Full article

Objective: Adipose tissue inflammation in obesity promotes insulin resistance and metabolic disease. The Duffy Antigen Receptor for Chemokines (DARC), a non-signaling receptor expressed on erythrocytes and on other cell types, modulates inflammation by regulating chemokine levels. Gene variants that affect DARC expression on erythrocytes are common in people of African descent. Here, we disrupted DARC expression in hematopoietic cells and adipocytes to determine the impact on obesity. Methods: DARC floxed mice were bred with vav1-Cre mice to disrupt DARC expression in hematopoietic cells (DARC^Δhemato), and with adipoq-Cre mice to disrupt DARC expression in adipocytes (DARC^Δadipo). Mice were fed a chow diet (CD) versus a high-fat diet (HFD) and studied in vivo. In vitro studies were conducted on preadipocytes isolated from wild-type (WT) and global DARC knockout mice. Results: HFD-fed DARC^Δhemato mice exhibited impaired glucose tolerance compared with WT littermates, independent of weight gain. This was associated with increased adipose tissue inflammation and systemic oxidative stress. DARC^Δadipo mice exhibited similar glucose tolerance but had subtle differences in adipose depot mass and adipocyte size compared with WT littermates. Deletion of DARC in preadipocytes had no impact on adipogenic differentiation or lipid accumulation in vitro. Similarly, endothelial-specific DARC KO mice also showed no differences in glucose tolerance compared with WT. Conclusions: DARC disruption in hematopoietic cells is associated with adipose tissue inflammation and alters glucose homeostasis during diet-induced obesity, accompanied by reduced circulating levels of several DARC-binding chemokines. The relevance of these findings to human DARC genetic variants and obesity-related metabolic disease warrants further investigation. Full article

Early-life stress and post-weaning exposure to a high-fat diet (HFD) have been independently associated with renal abnormalities; however, little is known about how these stressors interact to increase renal susceptibility to subsequent metabolic challenges. Therefore, this study evaluated the effects of early-life stress induced by maternal separation (MS) and post-weaning HFD on renal structure and function in male C57BL/6 mice. Animals were subjected to MS or remained unmanipulated (UM) and were subsequently fed a control diet (CD) or HFD until postnatal day 133, generating four experimental groups: UM-CD, UM-HFD, MS-CD, and MS-HFD. Renal structure was assessed by renal mass, histological analysis of the renal corpuscle, stereological quantification of glomerular numerical density (Nv) and individual glomerular volume (IGV), whereas renal function was evaluated by diuresis. MS and HFD independently increased renal mass, altered diuresis, reduced glomerular Nv, and promoted glomerular hypertrophy. Histological analysis revealed mesangial expansion, narrowing of the capsular space, focal capillary obliteration, and glomeruloparietal synechiae, which were pronounced in the MS-HFD group. Two-way ANOVA showed independent effects on Nv and a significant interaction for IGV. Reduced Nv correlated with increased IGV and diuresis. These findings indicate that early-life stress and post-weaning HFD promote complementary mechanisms of glomerular remodeling, increasing susceptibility to metabolically induced renal injury. Full article

A high-fat diet (HFD) promotes lipid metabolic disorders, chronic low-grade inflammation and skeletal muscle dysfunction. Kukoamine B (KB), a Lycium-derived polyamine alkaloid with reported anti-inflammatory and antioxidant activities, may protect against HFD-associated muscle impairment. C57BL/6J mice were fed an HFD and orally administered KB for 12 weeks. Muscle function was evaluated using inverted grid, forelimb grip strength and treadmill exhaustion tests. Histological, transcriptomic, ELISA, immunofluorescence and Western blot analyses were used to assess muscle injury and inflammatory signalling. KB reduced intramuscular lipid deposition, collagen accumulation and myofibre damage, improved muscle strength and exercise endurance, and partially restored AKT/mTOR-associated protein metabolic signalling. Transcriptomic analysis showed that KB downregulated HFD-activated inflammatory responses, chemokine signalling, lipopolysaccharide responses and Toll-like receptor-related pathways. KB also reduced plasma and skeletal muscle LPS levels, inhibited TLR4/MyD88/NF-κB signalling, and decreased TNF-α and IL-1β expression. TAK-242 mimicked the anti-inflammatory and muscle function-improving effects of KB, whereas their combination produced no statistically detectable additional effect under the conditions tested. These findings suggest that KB attenuates HFD-induced skeletal muscle dysfunction, potentially involving reduced LPS burden and suppression of TLR4/NF-κB-mediated metabolic inflammation. Full article

Background/Objectives: Sarcopenia is an age-associated skeletal muscle disorder that may be aggravated by a high-fat diet (HFD). Given the multifactorial pathogenesis of sarcopenia, single-nutrient interventions may be insufficient. This study investigated whether a specialized multinutrient formula could attenuate muscle dysfunction and intramuscular lipid accumulation in adult mice under standard-diet and HFD-fed conditions. Methods: Male C57BL/6J mice were assigned to five groups: young control (YC), adult control (OC), adult control supplemented with the nutritional formula (OCN), adult HFD-fed mice (OH), and adult HFD-fed mice supplemented with the formula (OHN). A specialized multinutrient formula containing enriched whey protein, β-glucan, antioxidant vitamins, and essential trace minerals was orally administered five times per week for 12 weeks. Body composition, muscle histology, grip strength, intramuscular lipid accumulation, inflammatory gene expression, and protein markers related to caspase-associated apoptosis, proteolysis-related signaling, and tissue remodeling were assessed. Results: Compared with YC mice, adult control and HFD-fed mice exhibited reduced muscle strength and fiber cross-sectional area, increased adiposity, intramuscular lipid deposition, elevated TNF-α expression, and alterations in selected protein markers related to caspase-associated apoptosis, proteolysis-related signaling, and tissue remodeling. Nutritional supplementation improved muscle strength and fiber morphology, reduced intramuscular lipid deposition, lowered TNF-α expression, reduced cleaved caspase marker abundance, decreased p38 MAPK and MuRF-1 expression, and increased collagen type III expression. Conclusions: HFD aggravated muscle dysfunction and sarcopenic obesity-related features in adult mice, as evidenced by impaired muscle function, reduced muscle fiber cross-sectional area, increased intramuscular lipid accumulation, and changes in selected inflammatory, cleaved caspase-, protein turnover-related, and remodeling markers. Nutritional supplementation mitigated these alterations and improved muscle structure and function. Full article

High-fat diet (HFD)-induced skeletal muscle atrophy is characterized by impaired muscle mass and function, mitochondrial dysfunction, redox imbalance, and increased inflammation. Previous research has shown that aerobic exercise ameliorates HFD-induced skeletal muscle atrophy, but the underlying mechanisms remain unclear. Dynamin-related protein 1 (Drp1) is a key GTPase that mediates mitochondrial fission, maintains mitochondrial homeostasis, and regulates reactive oxygen species (ROS) production and inflammatory responses. This study investigated the potential involvement of Drp1-associated mitochondrial fission in the protective effects of aerobic exercise against HFD-induced skeletal muscle atrophy. HFD-fed mice underwent an 8-week aerobic exercise intervention, and Mdivi-1, a commonly used mitochondrial fission inhibitor, was administered intraperitoneally to further examine the involvement of mitochondrial fission. Assessments included grip strength, endurance testing, body composition, histology, transmission electron microscopy, immunofluorescence, DHE staining, antioxidant assays, Western blotting, and qPCR. Aerobic exercise reduced Drp1 phosphorylation, oxidative stress, and inflammatory responses in the skeletal muscle of HFD-fed mice and attenuated skeletal muscle atrophy. Mdivi-1 treatment produced similar protective effects, including attenuation of skeletal muscle atrophy, oxidative stress, and inflammatory responses. Together, these findings suggest that Drp1 phosphorylation and associated mitochondrial fission may contribute to the protective effects of aerobic exercise against HFD-induced skeletal muscle atrophy. Full article

Metformin is a widely prescribed antidiabetic agent with pleiotropic effects extending beyond glycemic control, including anti-inflammatory and antioxidant actions. However, its impact on cytokine signaling and ferroptosis-related pathways in brown adipose tissue (BAT) remains poorly characterized. Here, we examined the transcriptional and metabolic responses to metformin in brown adipocytes and in a diet-induced obesity model. Differentiated brown adipocytes were treated with metformin and analyzed by RNA sequencing and RT-qPCR. C57BL/6 male mice fed a high-fat diet (HFD) were administered metformin to assess systemic metabolic parameters and BAT-specific responses, with validation by histology, RT-qPCR, and Western blot. Transcriptomic profiling identified differentially expressed genes enriched in cytokine–cytokine receptor interaction and ferroptosis-related KEGG pathways. Metformin modulated the expression of multiple inflammatory cytokine genes and upregulated antioxidant and ferroptosis defense-related genes, including the glutathione biosynthesis genes Gclc and Gclm, together with Hmox1, Gpx4, Nfe2l2 (Nrf2), and Slc7a11. Among these, Gpx4 showed the most consistent upregulation across mRNA and protein levels in BAT. In HFD-fed mice, metformin improved glucose tolerance and elevated the expression of antioxidant and ferroptosis-related genes in BAT, consistent with the in vitro findings. Together, these results indicate that metformin coordinately modulates antioxidant and ferroptosis defense-related gene expression in BAT, suggesting a tissue-protective transcriptional program under metabolic stress. Our findings identify candidate immunometabolic and ferroptosis-related targets of metformin in BAT and provide a basis for further mechanistic investigation of its tissue-specific actions beyond glycemic control. Full article

Background: Hyperlipidemia is a major risk factor for cardiometabolic disorders, including non-alcoholic fatty liver disease (NAFLD), and is closely associated with oxidative stress. Opuntia ficus-indica (OFI) cladodes are recognized as a rich source of bioactive phytochemicals; however, the molecular mechanisms underlying their metabolic benefits remain incompletely understood. Objectives: This study aimed to comprehensively evaluate the hypolipidemic and hepatoprotective potential of a polyphenol-rich O. ficus-indica cladode extract (OCE) using an integrated approach combining in vivo evaluation, untargeted metabolomics (UHPLC-Orbitrap-MS/MS), molecular docking, and ADMET prediction. Methods: Hyperlipidemic mice fed a high-fat diet (HFD) were treated with OCE, while molecular docking was performed on ten major annotated phytochemicals against twelve key proteins involved in lipid metabolism and cholesterol homeostasis, including HMGCR, FAS, PPARα, PCSK9, and NPC1L1, using simvastatin as the reference compound. Results: OCE treatment significantly improved plasma and hepatic lipid profiles, improved glucose homeostasis, and markedly reduced hepatic malondialdehyde (MDA) levels, indicating attenuation of oxidative stress. Histopathological analysis further supported a pronounced hepatoprotective effect, with a substantial reduction in hepatic steatosis. Untargeted metabolomics enabled the annotation of 102 metabolites, putatively identifying piscidic acid as the predominant phenolic constituent together with a diverse profile of flavonoids and phenolic acids. Molecular docking supported the potential contribution of these phytochemicals to the regulation of lipid metabolism through favorable interactions with multiple therapeutic targets, while ADMET prediction suggested an overall favorable pharmacokinetic and toxicity profile despite the lower intestinal permeability predicted for glycosylated derivatives. Conclusions: Overall, these findings support O. ficus-indica cladodes as a promising source of dietary bioactive compounds with potential applications in the nutritional management and prevention of hyperlipidemia and related cardiometabolic disorders. Full article

Obesity is a chronic metabolic disorder closely associated with dyslipidemia, insulin resistance, low-grade inflammation, and gut microbiota dysbiosis. Mulberry leaves are rich in bioactive proteins, but whether mulberry leaf albumin-type protein can improve diet-induced obesity remains unclear. In this study, ultrafiltered mulberry leaf albumin-type protein (UMP) was prepared and its anti-obesity effects were evaluated in high-fat diet (HFD)-fed C57BL/6J mice. UMP contained 87.12 ± 0.52 g/100 g protein, 2.52 ± 0.00 g/100 g polyphenols, and 8.21 ± 1.49 g/100 g polysaccharides, with two major albumin-type protein bands of approximately 14 and 52 kDa. Structural analysis showed that UMP was mainly composed of β-turns and α-helices. In HFD-fed mice, daily administration of UMP for 16 weeks reduced body weight gain by 3.85 g and 5.63 g in the low- and high-dose groups, respectively, without affecting food intake. Biochemical assays, glucose and insulin tolerance tests, and histological analysis showed that UMP improved insulin responsiveness, alleviated serum dyslipidemia, reduced hepatic lipid accumulation, and decreased circulating alanine aminotransferase, aspartate aminotransferase, and lipopolysaccharide levels. Histological analysis and nuclear magnetic resonance-based short-chain fatty acid quantification further showed that UMP protected colonic morphology and increased colonic short-chain fatty acid levels. Gut microbiota analysis showed that UMP restored microbial diversity, reduced the Firmicutes/Bacteroidota ratio, and enriched potentially beneficial genera, including Ileibacterium and norank_f_Muribaculaceae. Fecal biochemical assays suggested that UMP promoted fecal free fatty acid excretion and partially improved bile acid-related metabolic alterations. Untargeted serum metabolomics revealed that UMP reshaped metabolic pathways related to lipid turnover, bile acid signaling, glucose utilization, and glucuronidation. Correlation analysis linked UMP-enriched bacterial taxa with key metabolites involved in fatty acid and energy metabolism. Together, these findings indicate that UMP attenuates HFD-induced obesity through coordinated regulation of gut microbiota, intestinal metabolites, and systemic metabolic homeostasis. UMP may therefore represent a promising functional dietary protein for the prevention of obesity-related metabolic disorders. Full article

Adverse childhood experiences are associated with long-term metabolic disturbances, yet their effects on the exocrine pancreas remain poorly understood. Using maternal separation (MS) as a model of early-life stress, this study examined whether MS modifies the exocrine pancreatic response to a post-weaning high-fat diet (HFD) in male C57BL/6 mice. Animals were exposed to MS or standard rearing conditions and fed a control diet or HFD for 16 weeks. Body and pancreatic mass, plasma amylase and lipase activities, exocrine pancreatic histopathology, and apoptosis were assessed. HFD increased body mass and reduced the pancreas-to-body mass ratio independently of MS, without altering absolute pancreatic mass. Lipase activity increased significantly in response to both MS and HFD, whereas amylase showed a non-significant upward trend. Histopathological analysis revealed condition-dependent exocrine pancreatic remodeling, including acinar hypertrophy, autophagic vacuolization, focal necrosis, vascular alterations, interstitial edema, and ductal changes. These alterations were mild in HFD-only mice but more pronounced in MS-exposed animals, particularly when combined with HFD. Apoptosis was strongly influenced by early-life stress and modulated by diet, with significant effects of MS and the MS × diet interaction. Overall, early-life stress induces persistent structural and functional alterations in the exocrine pancreas, increasing susceptibility to nutritional challenges in adulthood. Full article

Background: Diets high in fat and carbohydrates, like fructose, trigger colon inflammation, increase intestinal permeability, and drive dysbiosis. However, the effects of obesogenic diets on gut microbiota, including Clostridium and Bacteroides, remain unknown. Understanding how these diets damage the colon is critical. Methods: Using a controlled preclinical obesity model, we compared the effects over time of High-Fat Diet (HFD), High-Fructose Diet (HFrD), and their combination (HFHFrD). Diet-induced dysbiosis was assessed at 4 and 8 weeks via qPCR using primers specific to bacterial phyla and species. In addition, intestinal inflammation, atrophy, and mucin production were evaluated by digital pathology after 8 weeks of diet exposure. Results: both HFrD and HFHFrD mice exhibited marked intestinal inflammation, atrophy, and damage, alongside altered production of neutral and mixed mucins. HFD-fed mice displayed a 15-fold surge in Clostridium/Bacteroides ratio at 4 weeks. At 8 weeks, HFrD-fed mice showed a striking 10-fold rise in microbial relative abundance compared to the other diets. Both HFrD and HFHFrD triggered an early increase in Bacteroides species, but significance emerged only at 8 weeks. Conclusions: Although all obesogenic diets induced inflammation, atrophy, epithelial damage, and altered mucin patterns, HFrD and HFHFrD caused pronounced disruptions to barrier function and dysbiosis. Critically, HFD consistently raised the Firmicutes/Bacteroidetes ratio at 4 and 8 weeks, while the Clostridium/Bacteroides ratio spiked only at 4 weeks. Obesogenic diets fundamentally shifted microbial load and diversity. Therefore, bacterial ratios, such as Clostridium/Bacteroides, may signal dysbiosis and tissue damage from obesogenic diets, but further research is required for confirmation. Full article

Objective: While Sanzi Sijun Formula (SSF) has exhibited preliminary efficacy against metabolic dysfunction-associated steatotic liver disease (MASLD), its mode of action remains undefined. This study therefore aimed to unravel its core therapeutic mechanisms. Methods: UPLC-MS was employed to characterize the major components of SSF. Male C57BL/6J mice were fed a high-fat diet combined with high-fructose/glucose drinking water (HFD-HF/G) for 10 weeks to establish a MASLD model, followed by SSF intervention. After 8-week treatment, body and liver weight, hepatic histopathological alterations, serum levels of lipids, transaminase, and inflammatory cytokines were detected, and transcriptomic sequencing was performed on mouse liver tissues for mechanistic exploration. AML12 hepatocytes stimulated with palmitic acid (PA) were treated with SSF alone or in combination with AMPK or SIRT1 specific inhibitors. RT-qPCR and Western blotting were used to detect the expression or activation levels of AMPK, SIRT1, and key lipid metabolism-related molecules. Results: A total of 77 active components were identified in SSF by UPLC-MS analysis. In MASLD model mice, SSF significantly reduced body and liver weight, serum levels of total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-c), and alanine aminotransferase (ALT), suppressed the pro-inflammatory cytokines including TNF-α and IL-6, and elevated adiponectin levels. Histopathological staining demonstrated that SSF effectively alleviated hepatic steatosis, ballooning, and inflammatory cell infiltration. Transcriptomic profiling analysis verified the major regulatory effect of SSF on lipid metabolism and identified the AMPK/SIRT1 signaling pathway as a potential mechanism. Further experiments confirmed that SSF restored the levels of AMPK/ACC phosphorylation and SIRT1 expression, thereby modulating downstream lipid metabolism-related genes in liver tissues. In PA-induced AML12 cells, SSF significantly reduced intracellular accumulation of lipid and reactive oxygen species (ROS), which were partially abrogated by the inhibitors of AMPK or SIRT1. Conclusions: SSF exerts prominent effects against MASLD in both in vivo and in vitro models. Modulation of the AMPK/SIRT1 signaling pathway primarily contributes to its therapeutic mechanism against lipid metabolism disorder and lipotoxic liver injury. These findings provide experimental evidence to support the clinical application of SSF for MASLD treatment. Full article

Cold-inducible RNA-binding protein (CIRP/CIRBP) is recognized as an extracellular damage-associated molecular pattern. However, its relationship to endothelial redox-inflammatory injury in atherosclerosis remains poorly characterized. Here, we explored the associations among CIRP, endothelial dysfunction, and TLR4-/SIRT6-related changes. In high-fat diet (HFD)-fed ApoE^−/− mice, circulating CIRP was elevated and positively correlated with atherosclerotic plaque burden. This increase coincided with systemic redox imbalance, impaired NO/eNOS activity, and vascular inflammation. In HUVECs, CIRP exposure reduced cell viability and impaired NO/eNOS function. These effects were accompanied by increased ROS accumulation and MDA content, together with reduced GSH-Px activity. CIRP also increased inflammatory cytokine production, NF-κB p65 phosphorylation, and THP-1 adhesion. At the molecular level, CIRP reduced SIRT6 expression. Overexpression of SIRT6 attenuated CIRP-induced endothelial injury, oxidative stress, and NO/eNOS dysfunction. CIRP also increased TLR4 expression. Accordingly, pharmacological TLR4 inhibition with TAK-242 attenuated CIRP-associated endothelial injury and partially restored SIRT6 expression and protein stability. Conversely, SIRT6 silencing weakened the protective effects of TAK-242. In addition, CIRP exposure was accompanied by increased overall eNOS acetylation. This increase was attenuated by TAK-242 and further enhanced by SIRT6 silencing. Exploratory cross-context transcriptomic analysis identified overlapping inflammatory and oxidative stress-related signatures. Representative antioxidant-related changes were further examined in CIRP-treated HUVECs through assessment of GPX4 and CAT mRNA expression and CAT activity. Finally, in a preliminary clinical cohort, serum CIRP levels were higher in patients with coronary heart disease and were positively associated with Gensini score, including selected exploratory multivariable models. Overall, these findings provide preliminary evidence that CIRP is associated with redox-inflammatory endothelial injury. The results are also consistent with the possible involvement of TLR4-/SIRT6-related signaling. These observations should be interpreted cautiously because of the relatively high CIRP concentration used in vitro, the cross-context transcriptomic comparison, and the small clinical cohort. Full article

An abnormality of Ca²⁺ signaling may aggravate lipid accumulation in steatotic hepatocytes, leading to non-alcoholic fatty liver disease. However, the molecular identity of Ca²⁺-permeable channels and the mechanism of involvement of these channels in steatotic hepatocytes are not well-studied. In the present study, we investigated the role of a Ca²⁺-permeable channel TRPM2 in lipid metabolism in steatotic hepatocytes. A mouse model of non-alcoholic fatty liver disease was established by high-fat-diet feeding. Fat accumulation, fibrosis, lipophagic indexes, TFEB and lysosomal acid lipase in the liver tissue and/or hepatocytes were compared between TRPM2-knockout mice and wild-type mice. Knockout of the TRPM2 gene aggravated liver fat accumulation and fibrosis. Mechanistically, the TRPM2 knockout impaired the lipophagic process, decreased lysosomal abundance and attenuated lysosomal/autolysosomal acidification in mouse hepatocytes. Furthermore, the TRPM2 knockout reduced TFEB expression and its nuclear translation and also reduced the expression/activity of lysosomal acid lipase. These data demonstrate that TRPM2 deficiency may reduce lipophagy via its action on TFEB and lysosomal acid lipase, consequently contributing to liver steatosis and NAFLD under high-fat feeding conditions. Full article