Inflammatory liver diseases and susceptibility to sepsis.

Patients with inflammatory liver diseases, particularly alcohol-associated liver disease and metabolic dysfunction-associated fatty liver disease (MAFLD), have higher incidence of infections and mortality rate due to sepsis. The current focus in the development of drugs for MAFLD is the resolution of non-alcoholic steatohepatitis and prevention of progression to cirrhosis. In patients with cirrhosis or alcoholic hepatitis, sepsis is a major cause of death. As the metabolic center and a key immune tissue, liver is the guardian, modifier, and target of sepsis. Septic patients with liver dysfunction have the highest mortality rate compared with other organ dysfunctions. In addition to maintaining metabolic homeostasis, the liver produces and secretes hepatokines and acute phase proteins (APPs) essential in tissue protection, immunomodulation, and coagulation. Inflammatory liver diseases cause profound metabolic disorder and impairment of energy metabolism, liver regeneration, and production/secretion of APPs and hepatokines. Herein, the author reviews the roles of (1) disorders in the metabolism of glucose, fatty acids, ketone bodies, and amino acids as well as the clearance of ammonia and lactate in the pathogenesis of inflammatory liver diseases and sepsis; (2) cytokines/chemokines in inflammatory liver diseases and sepsis; (3) APPs and hepatokines in the protection against tissue injury and infections; and (4) major nuclear receptors/signaling pathways underlying the metabolic disorders and tissue injuries as well as the major drug targets for inflammatory liver diseases and sepsis. Approaches that focus on the liver dysfunction and regeneration will not only treat inflammatory liver diseases but also prevent the development of severe infections and sepsis.

Multiomics Analysis of PCB126's Effect on a Mouse Chronic-Binge Alcohol Feeding Model.

BACKGROUND: Environmental pollutants, including polychlorinated biphenyls (PCBs) have been implicated in the pathogenesis of liver disease. Our group recently demonstrated that PCB126 promoted steatosis, hepatomegaly, and modulated intermediary metabolism in a rodent model of alcohol-associated liver disease (ALD). OBJECTIVE: To better understand how PCB126 promoted ALD in our previous model, the current study adopts multiple omics approaches to elucidate potential mechanistic hypotheses. METHODS: Briefly, male C57BL/6J mice were exposed to 0.2mg/kg polychlorinated biphenyl (PCB) 126 or corn oil vehicle prior to ethanol (EtOH) or control diet feeding in the chronic-binge alcohol feeding model. Liver tissues were collected and prepared for mRNA sequencing, phosphoproteomics, and inductively coupled plasma mass spectrometry for metals quantification. RESULTS: Principal component analysis showed that PCB126 uniquely modified the transcriptome in EtOH-fed mice. EtOH feeding alone resulted in >4,000 differentially expressed genes (DEGs), and PCB126 exposure resulted in more DEGs in the EtOH-fed group (907 DEGs) in comparison with the pair-fed group (503 DEGs). Top 20 significant gene ontology (GO) biological processes included "peptidyl tyrosine modifications," whereas top 25 significantly decreasing GO molecular functions included "metal/ion/zinc binding." Quantitative, label-free phosphoproteomics and western blot analysis revealed no major significant PCB126 effects on total phosphorylated tyrosine residues in EtOH-fed mice. Quantified hepatic essential metal levels were primarily significantly lower in EtOH-fed mice. PCB126-exposed mice had significantly lower magnesium, cobalt, and zinc levels in EtOH-fed mice. DISCUSSION: Previous work has demonstrated that PCB126 is a modifying factor in metabolic dysfunction-associated steatotic liver disease (MASLD), and our current work suggests that pollutants also modify ALD. PCB126 may, in part, be contributing to the malnutrition aspect of ALD, where metal deficiency is known to contribute and worsen prognosis. https://doi.org/10.1289/EHP14132.

Role of prostaglandin E2 and its receptors in chronic liver disease.

Chronic liver disease (CLD) is a major global health burden in terms of growing morbidity and mortality. Although many conditions can cause CLD, leading to cirrhosis and hepatocellular carcinoma (HCC), viral hepatitis, drug-induced liver injury (DILI), alcoholic liver disease (ALD) and non-alcoholic fatty liver disease (NAFLD) are the most common culprits. Prostaglandin E2 (PGE2), produced in the liver, is an important lipid mediator derived from the ω-6 polyunsaturated fatty acid, arachidonic acid, and plays a critical role in hepatic homeostasis. The physiological effects of PGE2 are mediated through four classes of E-type prostaglandin (EP) receptors, namely EP1, EP2, EP3 and EP4. In recent years, an increasing number of studies has been done to clarify the effects of PGE2 and EP receptors in regulating liver function and the pathogenesis of CLD to create a new potential clinical impact. In this review, we overview the biosynthesis and regulation of PGE2 and discuss the role of its synthesizing enzymes and receptors in the maintenance of normal liver function and the development and progress of CLD. We also discuss the potential of the PGE2-EP receptors system in treating CLD with various etiologies.

The effect of STAT1, miR-99b, and MAP2K1 in alcoholic liver disease (ALD) mouse model and hepatocyte.

Alcoholic liver disease (ALD) serves as the leading cause of chronic liver diseases-related morbidity and mortality, which threatens the life of millions of patients in the world. However, the molecular mechanisms underlying ALD progression remain unclear. Here, we applied microarray analysis and experimental approaches to identify miRNAs and related regulatory signaling that associated with ALD. Microarray analysis identified that the expression of miR-99b was elevated in the ALD mouse model. The AML-12 cells were treated with EtOH and the expression of miR-99b was enhanced in the cells. The expression of miR-99b was positively correlated with ALT levels in the ALD mice. The microarray analysis identified the abnormally expressed mRNAs in ALD mice and the overlap analysis was performed with based on the differently expressed mRNAs and the transcriptional factors of miR-99b, in which STAT1 was identified. The elevated expression of STAT1 was validated in ALD mice. Meanwhile, the treatment of EtOH induced the expression of STAT1 in the AML-12 cells. The expression of STAT1 was positively correlated with ALT levels in the ALD mice. The positive correlation of STAT1 and miR-99b expression was identified in bioinformatics analysis and ALD mice. The expression of miR-99b and pri-miR-99b was promoted by the overexpression of STAT1 in AML-12 cells. ChIP analysis confirmed the enrichment of STAT1 on miR-99b promoter in AML-12 cells. Next, we found that the expression of mitogen-activated protein kinase kinase 1 (MAP2K1) was negatively associated with miR-99b. The expression of MAP2K1 was downregulated in ALD mice. Consistently, the expression of MAP2K1 was reduced by the treatment of EtOH in AML-12 cells. The expression of MAP2K1 was negative correlated with ALT levels in the ALD mice. We identified the binding site of MAP2K1 and miR-99b. Meanwhile, the treatment of miR-99b mimic repressed the luciferase activity of MAP2K1 in AML-12 cells. The expression of MAP2K1 was suppressed by miR-99b in the cells. We observed that the expression of MAP2K1 was inhibited by the overexpression of STAT1 in AML-12 cells. Meanwhile, the apoptosis of AML-12 cells was induced by the treatment of EtOH, while miR-99b mimic promoted but the overexpression of MAP2K1 attenuated the effect of EtOH in the cells. In conclusion, we identified the correlation and effect of STAT1, miR-99b, and MAP2K1 in ALD mouse model and hepatocyte. STAT1, miR-99b, and MAP2K1 may serve as potential therapeutic target of ALD.

ERRγ-inducible FGF23 promotes alcoholic liver injury through enhancing CYP2E1 mediated hepatic oxidative stress.

Fibroblast growth factor 23 (FGF23) is a member of endocrine FGF family, along with FGF15/19 and FGF21. Recent reports showed that under pathological conditions, liver produces FGF23, although the role of hepatic FGF23 remains nebulous. Here, we investigated the role of hepatic FGF23 in alcoholic liver disease (ALD) and delineated the underlying molecular mechanism. FGF23 expression was compared in livers from alcoholic hepatitis patients and healthy controls. The role of FGF23 was examined in hepatocyte-specific knock-out (LKO) mice of cannabinoid receptor type 1 (CB1R), estrogen related receptor γ (ERRγ), or FGF23. Animals were fed with an alcohol-containing liquid diet alone or in combination with ERRγ inverse agonist. FGF23 is mainly expressed in hepatocytes in the human liver, and it is upregulated in ALD patients. In mice, chronic alcohol feeding leads to liver damage and induced FGF23 in liver, but not in other organs. FGF23 is transcriptionally regulated by ERRγ in response to alcohol-mediated activation of the CB1R. Alcohol induced upregulation of hepatic FGF23 and plasma FGF23 levels is lost in ERRγ-LKO mice, and an inverse agonist mediated inhibition of ERRγ transactivation significantly improved alcoholic liver damage. Moreover, hepatic CYP2E1 induction in response to alcohol is FGF23 dependent. In line, FGF23-LKO mice display decreased hepatic CYP2E1 expression and improved ALD through reduced hepatocyte apoptosis and oxidative stress. We recognized CBIR-ERRγ-FGF23 axis in facilitating ALD pathology through hepatic CYP2E1 induction. Thus, we propose FGF23 as a potential therapeutic target to treat ALD.

Poria cocos polysaccharides improve alcoholic liver disease by interfering with ferroptosis through NRF2 regulation.

The active ingredient in Poria cocos, a parasitic plant belonging to the family Polyporaceae, is Poria cocos polysaccharide (PCP). PCP exhibits liver protection and anti-inflammatory effects, although its effect on alcoholic liver disease (ALD) remains unstudied. This study investigated the mechanism of PCP in improving ALD by regulating the Nrf2 signaling pathway. After daily intragastric administration of high-grade liquor for 4 hours, each drug group received PCPs or the ferroptosis inhibitor ferrostatin-1. The Nrf2 inhibitor ML385 (100 mg/kg/day) group was intraperitoneally injected, after which PCP (100 mg/kg/day) was administered by gavage. Samples were collected after 6 weeks for liver function and blood lipid analysis using an automatic biochemical analyzer. In the alcoholic liver injury cell model established with 150 mM alcohol, the drug group was pretreated with PCP, Fer-1, and ML385, and subsequent results were analyzed. The results revealed that PCP intervention significantly reduced liver function and blood lipid levels in alcohol-fed rats, along with decreased lipid deposition. PCP notably enhanced Nrf2 signaling expression, regulated oxidative stress levels, inhibited NF-κß, and its downstream inflammatory signaling pathways. Furthermore, PCP upregulated FTH1 protein expression and reduced intracellular Fe2+, suggesting an improvement in ferroptosis. In vitro studies yielded similar results, indicating that PCP can reduce intracellular ferroptosis by regulating oxidative stress and improve alcoholic liver injury by inhibiting the production of inflammatory factors.

Cyanidin-3-O-Glucoside Alleviates Alcoholic Liver Injury via Modulating Gut Microbiota and Metabolites in Mice.

Alcoholic liver disease (ALD) is primarily caused by long-term excessive alcohol consumption. Cyanidin-3-O-glucoside (C3G) is a widely occurring natural anthocyanin with multiple biological activities. This study aims to investigate the effects of C3G isolated from black rice on ALD and explore the potential mechanism. C57BL/6J mice (male) were fed with standard diet (CON) and Lieber-DeCarli liquid-fed (Eth) or supplemented with a 100 mg/kg/d C3G Diet (Eth-C3G), respectively. Our results showed that C3G could effectively ameliorate the pathological structure and liver function, and also inhibited the accumulation of liver lipids. C3G supplementation could partially alleviate the injury of intestinal barrier in the alcohol-induced mice. C3G supplementation could increase the abundance of Norank_f_Muribaculaceae, meanwhile, the abundances of Bacteroides, Blautia, Collinsella, Escherichia-Shigella, Enterococcus, Prevotella, [Ruminococcus]_gnavus_group, Methylobacterium-Methylorubrum, Romboutsia, Streptococcus, Bilophila, were decreased. Spearman's correlation analysis showed that 12 distinct genera were correlated with blood lipid levels. Non-targeted metabolic analyses of cecal contents showed that C3G supplementation could affect the composition of intestinal metabolites, particularly bile acids. In conclusion, C3G can attenuate alcohol-induced liver injury by modulating the gut microbiota and metabolites, suggesting its potential as a functional food ingredient against alcoholic liver disease.

Regulation of the Nur77-P2X7r Signaling Pathway by Nodakenin: A Potential Protective Function against Alcoholic Liver Disease.

Alcoholic liver disease (ALD) is the main factor that induces liver-related death worldwide and represents a common chronic hepatopathy resulting from binge or chronic alcohol consumption. This work focused on revealing the role and molecular mechanism of nodakenin (NK) in ALD associated with hepatic inflammation and lipid metabolism through the regulation of Nur77-P2X7r signaling. In this study, an ALD model was constructed through chronic feeding of Lieber-DeCarli control solution with or without NK treatment. Ethanol (EtOH) or NK was administered to AML-12 cells, after which Nur77 was silenced. HepG2 cells were exposed to ethanol (EtOH) and subsequently treated with recombinant Nur77 (rNur77). Mouse peritoneal macrophages (MPMs) were treated with lipopolysaccharide/adenosine triphosphate (LPS/ATP) and NK, resulting in the generation of conditioned media. In vivo, histopathological alterations were markedly alleviated by NK, accompanied by reductions in serum triglyceride (TG), aspartate aminotransferase (AST), and alanine aminotransferase (ALT) levels and the modulation of Lipin-1, SREBP1, and Nur77 levels in comparison to the EtOH-exposed group (p < 0.001). Additionally, NK reduced the production of P2X7r and NLRP3. NK markedly upregulated Nur77, inhibited P2X7r and Lipin-1, and promoted the function of Cytosporone B, a Nur77 agonist (p < 0.001). Moreover, Nur77 deficiency weakened the regulatory effect of NK on P2X7r and Lipin-1 inhibition (p < 0.001). In NK-exposed MPMs, cleaved caspase-1 and mature IL-1ß expression decreased following LPS/ATP treatment (p < 0.001). NK also decreased inflammatory-factor production in primary hepatocytes stimulated with MPM supernatant. NK ameliorated ETOH-induced ALD through a reduction in inflammation and lipogenesis factors, which was likely related to Nur77 activation. Hence, NK is a potential therapeutic approach to ALD.

Increased Intestinal Permeability and Decreased Resiliency of the Intestinal Barrier in Alcoholic Liver Disease.

INTRODUCTION: Only 20%-30% of individuals with alcohol use disorder (AUD) develop alcoholic liver disease (ALD). While the development of gut-derived endotoxemia is understood to be a required cofactor, increased intestinal permeability in ALD is not completely understood. METHODS: We recruited 178 subjects-58 healthy controls (HCs), 32 with ALD, 53 with AUD but no liver disease (ALC), and 35 with metabolic dysfunction-associated steatotic liver disease (MASLD). Intestinal permeability was assessed by a sugar cocktail as a percentage of oral dose. The permeability test was repeated after an aspirin challenge in a subset. RESULTS: Five-hour urinary lactulose/mannitol ratio (primarily representing small intestinal permeability) was not statistically different in HC, ALC, ALD, and MASLD groups ( P = 0.40). Twenty-four-hour urinary sucralose (representing whole gut permeability) was increased in ALD ( F = 5.3, P < 0.01) and distinguished ALD from ALC; 24-hour sucralose/lactulose ratio (primarily representing colon permeability) separated the ALD group ( F = 10.2, P < 0.01) from the MASLD group. After aspirin challenge, intestinal permeability increased in all groups and ALD had the largest increase. DISCUSSION: In a group of patients, we confirmed that (i) the ALD group has increased intestinal permeability compared with the HC, ALC, or MASLD group. In addition, because small bowel permeability (lactulose/mannitol ratio) is normal, the disruption of intestinal barrier seems to be primarily in the large intestine; (ii) decreased resiliency of intestinal barrier to injurious agents (such as NSAID) might be the mechanism for gut leak in subset of AUD who develop ALD.

S-Adenosylmethionine Negatively Regulates the Mitochondrial Respiratory Chain Repressor MCJ in the Liver.

MCJ (Methylation-Controlled J protein), an endogenous repressor of the mitochondrial respiratory chain, is upregulated in multiple liver diseases but little is known about how it is regulated. S-adenosylmethionine (SAMe), the biological methyl donor, is frequently depleted in chronic liver diseases. Here, we show that SAMe negatively regulates MCJ in the liver. While deficiency in methionine adenosyltransferase alpha 1 (MATα1), enzyme that catalyzes SAMe biosynthesis, leads to hepatic MCJ upregulation, MAT1A overexpression and SAMe treatment reduced MCJ expression. We found that MCJ is methylated at lysine residues and that it interacts with MATα1 in liver mitochondria, likely to facilitate its methylation. Lastly, we observed that MCJ is upregulated in alcohol-associated liver disease, a condition characterized by reduced MAT1A expression and SAMe levels along with mitochondrial injury. MCJ silencing protected against alcohol-induced mitochondrial dysfunction and lipid accumulation. Our study demonstrates a new role of MATα1 and SAMe in reducing hepatic MCJ expression.

Hepatocyte-specific mitogen-activated protein kinase phosphatase 1 in sexual dimorphism and susceptibility to alcohol induced liver injury.

Background: It is well established that females are more susceptible to the toxic effects of alcohol, although the exact mechanisms are still poorly understood. Previous studies noted that alcohol reduces the expression of mitogen-activated protein kinase phosphatase 1 (MKP1), a negative regulator of mitogen-activated protein kinases (MAPK) in the liver. However, the role of hepatocyte- specific MKP1 in the pathogenesis of alcohol-associated liver disease (ALD) remains uncharacterized. This study aimed to evaluate the role of hepatocyte-specific MKP1 in the susceptibility and sexual dimorphism in alcohol-induced liver injury. Methods: C57Bl/6 mice were used in an intragastric ethanol feeding model of alcohol-associated steatohepatitis (ASH). Hepatocyte-specific Mkp1-/- knockout and (Mkp1+/+ "f/f" male and female mice were subjected to the NIAAA chronic plus binge model. Primary mouse hepatocytes were used for in vitro studies. Liver RNA sequencing was performed on an Illumina NextSeq 500. Liver injury was evaluated by plasma alanine transaminase (ALT), hepatic ER stress and inflammation markers. Statistical analysis was carried out using ANOVA and the unpaired Student's t-test. Results: ASH was associated with the severe injury accompanied by increased endoplasmic reticulum (ER) stress and significant downregulation of Dusp1 mRNA expression. In vitro, ethanol treatment resulted in a time-dependent decrease in Dusp1 mRNA and protein expression in primary hepatocytes in both males and females; however, this effect was significantly more pronounced in hepatocytes from females. In vivo, female mice developed more liver injury in a chronic plus binge model which was accompanied by a significant decrease in liver Dusp1 mRNA expression. In comparison, liver Dusp1 was not changed in male mice, while they developed milder injury to alcohol. Mkp1 deletion in hepatocytes led to increased alcohol induced liver injury, ER stress and inflammation in both sexes. Conclusion: Hepatocyte Mkp1 plays a significant role in alcohol induced liver injury. Alcohol downregulates Mkp1 expression in hepatocytes in a sex dependent manner and could play a role in sexual dimorphism in increased female susceptibility to alcohol.

TXNIP in liver sinusoidal endothelial cells ameliorates alcohol-associated liver disease via nitric oxide production.

Dysregulation of liver sinusoidal endothelial cell (LSEC) differentiation and function has been reported in alcohol-associated liver disease (ALD). Impaired nitric oxide (NO) production stimulates LSEC capillarization and dysfunction; however, the mechanism underlying NO production remains unclear. Here, we investigated the role of thioredoxin-interacting protein (TXNIP), an important regulator of redox homeostasis, in endothelial cell NO production and its subsequent effects on ALD progression. We found that hepatic TXNIP expression was upregulated in patients with ALD and in ethanol diet-fed mice with high expression in LSECs. Endothelial cell-specific Txnip deficiency (TxnipΔEC) in mice exacerbated alcohol-induced liver injury, inflammation, fibrosis, and hepatocellular carcinoma development. Deletion of Txnip in LSECs led to sinusoidal capillarization, downregulation of NO production, and increased release of proinflammatory cytokines and adhesion molecules, whereas TXNIP overexpression had the opposite effects. Mechanistically, TXNIP interacted with transforming growth factor ß-activated kinase 1 (TAK1) and subsequently suppressed the TAK1 pathway. Inhibition of TAK1 activation restored NO production and decreased the levels of proinflammatory cytokines, thereby, blocking liver injury and inflammation in TxnipΔEC mice. Our findings indicate that upregulated TXNIP expression in LSECs serves a protective role in ameliorating ALD. Enhancing TXNIP expression could, therefore, be a potential therapeutic approach for ALD.

Gut-derived ammonia contributes to alcohol-related fatty liver development via facilitating ethanol metabolism and provoking ATF4-dependent de novo lipogenesis activation.

BACKGROUND & AIMS: Dysbiosis contributes to alcohol-associated liver disease (ALD); however, the precise mechanisms remain elusive. Given the critical role of the gut microbiota in ammonia production, we herein aim to investigate whether and how gut-derived ammonia contributes to ALD. METHODS: Blood samples were collected from human subjects with/without alcohol drinking. Mice were exposed to the Lieber-DeCarli isocaloric control or ethanol-containing diets with and without rifaximin (a nonabsorbable antibiotic clinically used for lowering gut ammonia production) supplementation for five weeks. Both in vitro (NH4Cl exposure of AML12 hepatocytes) and in vivo (urease administration for 5 days in mice) hyperammonemia models were employed. RNA sequencing and fecal amplicon sequencing were performed. Ammonia and triglyceride concentrations were measured. The gene and protein expression of enzymes involved in multiple pathways were measured. RESULTS: Chronic alcohol consumption causes hyperammonemia in both mice and human subjects. In healthy livers and hepatocytes, ammonia exposure upregulates the expression of urea cycle genes, elevates hepatic de novo lipogenesis (DNL), and increases fat accumulation. Intriguingly, ammonia promotes ethanol catabolism and acetyl-CoA formation, which, together with ammonia, synergistically facilitates intracellular fat accumulation in hepatocytes. Mechanistic investigations uncovered that ATF4 activation, as a result of ER stress induction and general control nonderepressible 2 activation, plays a central role in ammonia-provoked DNL elevation. Rifaximin ameliorates ALD pathologies in mice, concomitant with blunted hepatic ER stress induction, ATF4 activation, and DNL activation. CONCLUSIONS: An overproduction of ammonia by gut microbiota, synergistically interacting with ethanol, is a significant contributor to ALD pathologies.

The gut-liver axis perspective: Exploring the protective potential of polysaccharides from Cistanche deserticola against alcoholic liver disease.

The primary objective of this study is to investigate the potential mechanism behind the protective effect of Cistanche deserticola polysaccharides (CP) against alcoholic liver disease (ALD). Multiple chromography techniques were employed to characterize CP from polysaccharide, the molecular weight distribution of polysaccharides, monosaccharide composition, isomeric hydrogen and isomeric carbon, in order to clarify the material basis of CP. To create the ALD mouse model, we utilized the well-established Lieber-DeCarli alcoholic liquid feed method. Findings from the study revealed that CP administration resulted in significant improvements in intestinal permeability, upregulation of barrier proteins expression, and reduced levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in mouse liver and serum. Additionally, CP treatment reduced the presence of inflammatory cytokines both in serum and liver while enhancing the activity of antioxidant enzymes in the liver. Furthermore, CP effectively reduced alcohol-induced oxidative damage by downregulating Keap1 protein levels in the liver, leading to increased expression of Nrf2 protein. The 16S rDNA sequencing results revealed that CP significantly restored the intestinal microbiota composition in ALD mice. These findings establish a strong association between gut microbiota and liver injury indicators, highlighting the potential of CP in preventing and treating ALD by modulating the gut-liver axis.

Kefir Ameliorates Alcohol-Induced Liver Injury Through Modulating Gut Microbiota and Fecal Bile Acid Profile in Mice.

SCOPE: Alcoholic liver disease (ALD) is the leading cause of liver-related deaths worldwide. Kefir has been studied for its properties of anti-obesity, rebuilding intestinal homeostasis, and alleviating non-alcoholic fatty liver disease. However, the possible role of kefir in the prevention or treatment of ALD has not been carefully considered. Here, it evaluated the protective effects of kefir supplementation on alcohol-induced liver injury. METHODS AND RESULTS: C57BL/6J mice are fed to Lieber-DeCarli liquid diet containing alcohol to build ALD mouse model, followed by oral administration with kefir. Results indicate that kefir treatment improves liver pathological changes, decreases the expression levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) and inflammatory markers, and increases antioxidant levels. Kefir supplementation also restores the intestinal barrier and altered microbial composition, indicates as increases of Blautia, Bacteroides, and Parasutterella and decreases in the Firmicutes/Bacteroidetes (F/B) ratio and populations of Psychrobacter, Bacillus, and Monoglobus. Moreover, kefir supplementation decreases the levels of total bile acids (BAs) and primary BAs and increases the secondary/primary BA ratio. Gut microbes play a key role in the conversion of primary to secondary fecal BAs. CONCLUSION: Kefir can ameliorate ALD through regulating the composition of the gut microbiota.

Bioactive signalling lipids as drivers of chronic liver diseases.

Lipids are important in multiple cellular functions, with most having structural or energy storage roles. However, a small fraction of lipids exert bioactive roles through binding to G protein-coupled receptors and induce a plethora of processes including cell proliferation, differentiation, growth, migration, apoptosis, senescence and survival. Bioactive signalling lipids are potent modulators of metabolism and energy homeostasis, inflammation, tissue repair and malignant transformation. All these events are involved in the initiation and progression of chronic liver diseases. In this review, we focus specifically on the roles of bioactive lipids derived from phospholipids (lyso-phospholipids) and poly-unsaturated fatty acids (eicosanoids, pro-resolving lipid mediators and endocannabinoids) in prevalent chronic liver diseases (alcohol-associated liver disease, non-alcoholic fatty liver disease, viral hepatitis and hepatocellular carcinoma). We discuss the balance between pathogenic and beneficial bioactive lipids as well as potential therapeutic targets related to the agonism or antagonism of their receptors.

Preventive effect of low-carbohydrate high-fat dietary pattern on liver disease caused by alcohol consumption via a 6pgd-involved mechanism in mice.

A low-carbohydrate high-fat (LCHF) dietary pattern has been reported to improve chronic metabolic diseases. However, whether and how the LCHF diet affects the pathological progression in patients with alcohol-related liver diseases (ALD) is largely unknown. This study was conducted to evaluate the effect of the LCHF diet on ALD and clarify its potential mechanism(s). The ALD model was established by feeding C57BL/6N mice with a Lieber-DeCarli liquid alcohol diet with a modified carbohydrate/fat ratio under an isoenergetic pattern. After an eight-week intervention, we observed that the LCHF diet significantly reduced alcohol-induced hepatic steatosis and liver injury, along with improved lipid metabolic-related gene disorders and redox imbalance. The alcohol-stimulated increase in pro-inflammatory cytokine cytokines expression, including TNF-α, IL-1ß, and IL-6, was markedly reversed by the LCHF diet. Liver transcriptome sequencing and qPCR validation showed that twenty-four alcohol-disturbed genes were significantly reversed by LCHF-diet intervention. The top differentially expressed genes were selected for further investigation. Among them, 6-phosphogluconate dehydrogenase (6PGD) was significantly up-regulated by alcohol treatment in both the liver and cultured hepatocytes. Spearman correlation analysis revealed that 6PGD was positively associated with hepatic steatosis, liver injury, and oxidative stress indexes. In vitro, the 6PGD knockdown ameliorated alcohol-induced hepatotoxicity and intracellular lipid accumulation, as well as lipid metabolic-related gene disorders, implying the involvement of 6PGD in LCHF-protected ALD. In conclusion, LCHF diet intervention alleviated chronic alcohol consumption-induced liver dysfunction in mice. 6PGD is a potential novel target for ALD prevention that contributes to LCHF-improved ALD. A LCHF diet might be a promising choice for ALD management.

Gentiana Scabra Bge Extract (GSE) Protects Against Alcoholic Liver Disease by Regulating the TLR4/NF-κB Pathway in Mice.

BACKGROUND: Alcohol abuse leads to alcoholic liver disease (ALD), for which no effective treatment is yet known. Gentiana Scabra Bge is a traditional Chinese medicine; its extract has a significant liver protection effect, but its effects on the mechanism of improving alcohol-induced toxicity remain unclear. Therefore, this study used cell and mouse models to investigate how Gentiana Scabra Bge extract (GSE) might affect the TLT4/NF-κB inflammation pathway in ALD. METHODS: In mice, we induced the alcoholic liver injury model by applying alcohol and induced the inflammatory cell model by lipopolysaccharide (LPS)-induced macrophages. Using an enzyme-linked immunosorbent assay (ELISA) kit, aspartate aminotransferase (AST) and alanine aminotransferase (ALT), and interleukin 1ß (IL-1ß), interleukin 6 (IL-6), and tumor necrosis factor-α (TNF-α) levels were measured in liver tissue; we also performed histological analysis of liver tissue sections to assess the hepatoprotective effect of GSE on alcohol. Using real-time fluorescence quantification, we determined the expression of toll-like receptor 4 (TLR4) and nuclear factor κB (NF-κB) mRNA levels; we used Western blotting to detect the expression of TLR4/NF-κB signaling pathway-related proteins. RESULTS: We demonstrate that GSE decreased AST and ALT activity, ameliorated liver dysfunction, decreased cytokine levels, and reduced LPS-induced cellular inflammation. In addition, GSE protected mouse liver cells from the inflammatory response by reducing alcohol-induced liver pathological damage and downregulating genes and proteins such as nuclear factors. CONCLUSIONS: GSE can attenuate liver injury in mice through the TLR4/NF-κB pathway by inhibiting the activation of nuclear factors.

Astaxanthin Protects against Alcoholic Liver Injury via Regulating Mitochondrial Redox Balance and Calcium Homeostasis.

Increasing evidence points to the critical role of calcium overload triggered by mitochondrial dysfunction in the development of alcoholic liver disease (ALD). As an important organelle for aerobic respiration with a double-layered membrane, mitochondria are pivotal targets of alcohol metabolism-mediated lipid peroxidation, wherein mitochondria-specific phospholipid cardiolipin oxidation to 4-hydroxynonenal (4-HNE) ultimately leads to mitochondrial integrity and function impairment. Therefore, it is absolutely essential to identify effective nutritional intervention targeting mitochondrial redox function for an alternative therapy of ALD, in order to compensate for the difficulty in achieving alcohol withdrawal due to addiction. In this study, we confirmed the significant advantages of astaxanthin (AX) against alcohol toxicity among various carotenoids via cell experiments and identified the potential in mitochondrion morphogenesis and calcium signaling pathway by bioinformatics analysis. The ALD model of Sprague-Dawley (SD) rats was also generated to investigate the effectiveness of AX on alcohol-induced liver injury, and the underlying mechanisms were further explored. AX intervention attenuated alcohol-induced oxidative stress and lipid peroxidation as well as mitochondrial dysfunction characterized by degenerative morphology changes and collapsed membrane potential. Also, AX reduced the production of 4-HNE by activating the Nrf2-ARE signaling pathway, which is closely associated with the redox balance of mitochondria. In addition, relieved mitochondrial Ca2+ accumulation caused by AX was observed both in vivo and in vitro. Furthermore, we revealed the structure-activity relationship of AX and mitochondrial membrane channel proteins MCU and VDAC1, implying potential acting targets. Altogether, our data indicated a new mechanism of AX intervention which protects against alcohol-induced liver injury through restoring redox balance and Ca2+ homeostasis in mitochondria, as well as provided novel insights into the development of AX as a therapeutic option for the management of ALD.

S100a16 Deficiency Prevents Alcohol-induced Fatty Liver Injury via Inducing MANF Expression in Mice.

Alcoholic liver disease (ALD) encompasses conditions ranging from simple steatosis to cirrhosis and even liver cancer. It has gained significant global attention in recent years. Despite this, effective pharmacological treatments for ALD remain elusive, and the core mechanisms underlying the disease are not yet fully comprehended. S100A16, a newly identified calcium-binding protein, is linked to lipid metabolism. Our research has discovered elevated levels of the S100A16 protein in both serum and liver tissue of ALD patients. A similar surge in hepatic S100A16 expression was noted in a Gao-binge alcohol feeding mouse model. S100a16 knockdown alleviated ethanol-induced liver injury, steatosis and inflammation. Conversely, S100a16 transgenic mice showed aggravating phenomenon. Mechanistically, we identify mesencephalic astrocyte-derived neurotrophic factor (MANF) as a regulated entity downstream of S100a16 deletion. MANF inhibited ER-stress signal transduction induced by alcohol stimulation. Meanwhile, MANF silencing suppressed the inhibition effect of S100a16 knockout on ethanol-induced lipid droplets accumulation in primary hepatocytes. Our data suggested that S100a16 deletion protects mice against alcoholic liver lipid accumulation and inflammation dependent on upregulating MANF and inhibiting ER stress. This offers a potential therapeutic avenue for ALD treatment.