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Bile acid metabolism and signaling in liver disease and therapy

Liver Research.2017;1(1):3-9. doi:10.1016/j.livres.2017.05.001

Bile acids play a critical role in the regulation of glucose,lipid,and energy metabolism through activation of the nuclear bile acid receptor farnesoid X receptor(FXR)and membrane G protein-coupled bile acid receptor-1(Gpbar-1,aka TGR5).Agonist activation of FXR and TGR5 improves insulin and glucose sensitivity and stimulates energy metabolism to prevent diabetes,obesity,and non-alcoholic fatty liver disease(NAFLD).Bile acids have both pro-and anti-inflammatory actions through FXR and TGR5 in the intestine and liver.In the intestine,bile acids activate FXR and TGR5 to stimulate fibroblast growth factor 15 and glucagon-like peptide-1 secretion.FXR and TGR5 agonists may have therapeutic potential for treating liver-related metabolic diseases,such as diabetes and NAFLD.

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Bile acids as global regulators of hepatic nutrient metabolism

B.Hylemon PHILLIP ; Takabe KAZUAKI ; Dozmorov MIKHAIL ; Nagahashi MASAYUKI ; Zhou HUIPING

Liver Research.2017;1(1):10-16. doi:10.1016/j.livres.2017.03.002

Bile acids(BA)are synthesized from cholesterol in the liver.They are essential for promotion of the absorption of lipids,cholesterol,and lipid-soluble vitamins from the intestines.BAs are hormones that regulate nutrient metabolism by activating nuclear receptors(farnesoid X receptor(FXR),pregnane X receptor,vitamin D)and G protein-coupled receptors(e.g.,TGR5,sphingosine-1-phosphate receptor 2(S1PR2))in the liver and intestines.In the liver,S1PR2 activation by conjugated BAs activates the extracellular signal-regulated kinase 1/2 and AKT signaling pathways,and nuclear sphingosine kinase 2.The latter produces sphingosine-1-phosphate(S1P),an inhibitor of histone deacetylases 1/2,which al-lows for the differential up-regulation of expression of genes involved in the metabolism of sterols and lipids.We discuss here the emerging concepts of the interactions of BAs,FXR,insulin,S1P signaling and nutrient metabolism.

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Bile acid receptors link nutrient sensing to metabolic regulation

Li JIBIAO ; Li TIANGANG

Liver Research.2017;1(1):17-25. doi:10.1016/j.livres.2017.04.001

Non-alcoholic fatty liver disease(NAFLD)is a common liver disease in Western populations.Non-alcoholic steatohepatitis(NASH)is a more debilitating form of NAFLD characterized by hepatocellular injury and inflammation,which significantly increase the risk of end-stage liver and cardiovascular diseases.Unfortunately,there are no available drug therapies for NASH.Bile acids are physiological detergent molecules that are synthesized from cholesterol exclusively in the hepatocytes.Bile acids circulate between the liver and intestine,where they are required for cholesterol solubilization in the bile and dietary fat emulsification in the gut.Bile acids also act as signaling molecules that regulate metabolic homeostasis and inflammatory processes.Many of these effects are mediated by the bile acid-activated nuclear receptor farnesoid X receptor(FXR)and the G protein-coupled receptor TGR5.Nutrient signaling regulates hepatic bile acid synthesis and circulating plasma bile acid concentrations,which in turn control metabolic homeostasis.The FXR agonist obeticholic acid has had beneficial effects on NASH in recent clinical trials.Preclinical studies have suggested that the TGR5 agonist and the FXR/TGR5 dual agonist are also potential therapies for metabolic liver diseases.Extensive studies in the past few decades have significantly improved our understanding of the metabolic regulatory function of bile acids,which has provided the molecular basis for developing promising bile acid-based therapeutic agents for NASH treatment.

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Cellular crosstalk during cholestatic liver injury

Thomson JOANNE ; Hargrove LAURA ; Kennedy LINDSEY ; Demieville JENNIFER ; Francis HEATHER

Liver Research.2017;1(1):26-33. doi:10.1016/j.livres.2017.05.002

The functions of the liver are very diverse.From detoxifying blood to storing glucose in the form of glycogen and producing bile to facilitate fat digestion,the liver is a very active and important organ.The liver is comprised of many varied cell types whose functions are equally diverse.Cholangiocytes line the biliary tree and aid in transporting and adjusting the composition of bile as it travels to the gallbladder.Hepatic stellate cells and portal fibroblasts are located in different areas within the liver architecture,but both contribute to the development of fibrosis upon activation after liver injury.Vascular cells,including those that constitute the peribiliary vascular plexus,are involved in functions other than blood delivery to and from the liver,such as supporting the growth of the biliary tree during development.Mast cells are normally found in healthy livers but in very low numbers.However,after injury,mast cell numbers greatly increase as they infiltrate and release factors that exacerbate the fibrotic response.While not an all-inclusive list,these cells have individual roles within the liver,but they are also able to communicate with each other by cellular crosstalk.In this review,we examine some of these pathways that can lead to an increase in the homeostatic dysfunction seen in liver injury.

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Diagnostic and therapeutic potentials of microRNAs in cholangiopathies

Kennedy LINDSEY ; Francis HEATHER ; Meng FANYIN ; Glaser SHANNON ; Alpini GIANFRANCO

Liver Research.2017;1(1):34-41. doi:10.1016/j.livres.2017.03.003

Cholangiopathies are a group of rare,devastating diseases that arise from damaged cholangiocytes,the cells that line the intra-and extra-hepatic bile ducts of the biliary epithelium.Cholangiopathies result in significant morbidity and mortality and are a major cause of liver transplantation.A better understanding of the underlying pathogenesis that influences cholangiocyte dysregulation and cholangiopathy pro-gression is necessary,considering the dismal prognosis associated with these diseases. MicroRNAs are a class of small,non-coding RNAs that regulate post-transcriptional mRNA expression of specific genes.The role of microRNAs has expanded to include the initiation and development of many diseases,including cholangiopathies.Understanding microRNA regulation of cholangiopathies may provide diagnostic and therapeutic benefit for these diseases.In this review,the authors primarily focus on studies published within the last five years that help determine the diagnostic and therapeutic po-tential of microRNAs in cholangiopathies.

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New insights into the role of Lith genes in the formation of cholesterol-supersaturated bile

H.Wang HELEN ; Li TIANGANG ; Portincasa PIERO ; A.Ford DAVID ; A.Neuschwander-Tetri BRENT ; Tso PATRICK ; Q.-H.Wang DAVID

Liver Research.2017;1(1):42-53. doi:10.1016/j.livres.2017.05.005

Cholesterol gallstone formation represents a failure of biliary cholesterol homeostasis in which the physical-chemical balance of cholesterol solubility in bile is disturbed.Lithogenic bile is mainly caused by persistent hepatic hypersecretion of biliary cholesterol and sustained cholesterol-supersaturated bile is an essential prerequisite for the precipitation of solid cholesterol monohydrate crystals and the forma-tion of cholesterol gallstones.The metabolic determinants of the supply of hepatic cholesterol molecules that are recruited for biliary secretion are dependent upon the input-output balance of cholesterol and its catabolism in the liver.The sources of cholesterol for hepatic secretion into bile have been extensively investigated;however,to what extent each cholesterol source contributes to hepatic secretion is still unclear both under normal physiological conditions and in the lithogenic state.Although it has been long known that biliary lithogenicity is initiated by hepatic cholesterol hypersecretion,the genetic mecha-nisms that cause supersaturated bile have not been defined yet.Identification of the Lith genes that determine hepatic cholesterol hypersecretion should provide novel insights into the primary genetic and pathophysiological defects for gallstone formation.In this review article,we focus mainly on the path-ogenesis of the formation of supersaturated bile and gallstones from the viewpoint of genetics and pathophysiology.A better understanding of the molecular genetics and pathophysiology of the formation of cholesterol-supersaturated bile will undoubtedly facilitate the development of novel,effective,and noninvasive therapies for patients with gallstones,which would reduce the morbidity,mortality,and costs of health care associated with gallstones,a very prevalent liver disease worldwide.

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Adipose tissue autophagy and homeostasis in alcohol-induced liver injury

Li YUAN ; Ding WEN-XING

Liver Research.2017;1(1):54-62. doi:10.1016/j.livres.2017.03.004

Alcohol consumption leads to injury in multiple organs and systems,including the liver,brain,heart,skeletal muscle,pancreas,bone,immune system,and endocrine system.Emerging evidence indicates that alcohol also promotes adipose tissue dysfunction,which may contribute to injury progression in other organs and systems.Autophagy is a lysosomal degradation pathway that has been shown to regulate adipose tissue homeostasis and adipogenesis.Increasing evidence also demonstrates that alcohol consumption affects autophagy in multiple tissues.This review summarizes current knowledge regarding the effect of autophagy on adipose tissue and its potential roles in alcohol-induced adipose tissue atrophy as well as its contribution to alcohol-induced liver injury.

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Transgenic overexpression of steroid sulfatase alleviates cholestasis

Jiang MENGXI ; Xu MEISHU ; Ren SONGRONG ; W.Selcer KYLE ; Xie WEN

Liver Research.2017;1(1):63-69. doi:10.1016/j.livres.2017.03.001

Background and Aim:Sulfotransferase(SULT)-mediated sulfation and steroid sulfatase(STS)-mediated desulfation represent two critical mechanisms that regulate the chemical and functional homeostasis of endogenous and exogenous molecules.STS catalyzes the hydrolysis of steroid sulfates to form hydrox-ysteroids.Oxygenated cholesterol derivative oxysterols are known to be endogenous ligands of the liver X receptor(LXR),a nuclear receptor with anti-cholestasis activity,whereas the sulfated oxysterols antagonize LXR signaling.The conversion of sulfated oxysterols to their non-sulfated counterparts is catalyzed by STS.The aim of this study is to determine whether STS can alleviate cholestasis by increasing the activity of LXR. Methods:Liver-specific STS transgenic mice were created and subject to the lithocholic acid(LCA)-induced model of cholestasis. Results:Transgenic overexpression of STS in the liver promoted bile acid elimination and alleviated LCA-induced cholestasis.The protective effect of the STS transgene was associated with the activation of LXR and induction of LXR target genes,likely because of the increased conversion of the antagonistic oxy-sterol sulfates to the agonistic oxysterols. Conclusions:STS has a novel function in controlling the homeostasis of bile acids by regulating endog-enous LXR ligands.

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Silencing of α-complex protein-2 reverses alcohol-and cytokine-induced fibrogenesis in hepatic stellate cells

Liu HAO ; Chen ZHIJIN ; Jin WEI ; Barve ASHUTOSH ; Wan Yvonne YU-JUI ; Cheng KUN

Liver Research.2017;1(1):70-79. doi:10.1016/j.livres.2017.05.003

Background and aim:α-complex protein-2(αCP2)encoded by the poly(rC)binding protein 2(PCBP2)gene is responsible for the accumulation of type Ⅰ collagen in fibrotic livers.In this study,we silenced the PCBP2 gene using a small interfering RNA(siRNA)to reverse alcohol-and cytokine-induced profibrogenic effects on hepatic stellate cells(HSCs). Methods:Primary rat HSCs and the HSC-T6 cell line were used as fibrogenic models to mimic the initiation and perpetuation stages of fibrogenesis,respectively.We previously found that a PCBP2 siRNA,which efficiently silences expression of αCP2,reduces the stability of type Ⅰ collagen mRNA.We inves-tigated the effects of the PCBP2 siRNA on cell proliferation and migration.Expression of type Ⅰ collagen in HSCs was analyzed by quantitative real-time PCR and western blotting.In addition,we evaluated the effects of the PCBP2 siRNA on apoptosis and the cell cycle. Results:PCBP2 siRNA reversed multiple alcohol-and cytokine-induced profibrogenic effects on primary rat HSCs and HSC-T6 cells.The PCBP2 siRNA also reversed alcohol-and cytokine-induced accumulation of type Ⅰ collagen as well as cell proliferation and migration.Moreover,the combination of LY2109761,a transforming growth factor-β1 inhibitor,and the PCBP2 siRNA exerted a synergistic inhibitive effect on the accumulation of type Ⅰ collagen in HSCs. Conclusions:Silencing of PCBP2 using siRNA could be a potential therapeutic strategy for alcoholic liver fibrosis.

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Hepatic progenitor cell activation in liver repair

Bria ADAM ; Marda JORGENSEN ; Zhou JUNMEI ; Sun XIAOWEI ; Cao QI ; E.Petersen BRYON ; Pi LIYA

Liver Research.2017;1(2):81-87. doi:10.1016/j.livres.2017.08.002

The liver possesses an extraordinary ability to regenerate after injury.Hepatocyte-driven liver regener-ation is the default pathway in response to mild-to-moderate acute liver damage.When replication of mature hepatocytes is blocked,facultative hepatic progenitor cells(HPCs),also referred to as oval cells(OCs)in rodents,are activated.HPC/OCs have the ability to proliferate clonogenically and differentiate into several lineages including hepatocytes and bile ductal epithelia.This is a conserved liver injury response that has been studied in many species ranging from mammals(rat,mouse,and human)to fish.In addition,improper HPC/OC activation is closely associated with fibrotic responses,characterized by myofibroblast activation and extracellular matrix production,in many chronic liver diseases.Matrix remodeling and metalloprotease activities play an important role in the regulation of HPC/OC prolifer-ation and fibrosis progression.Thus,understanding molecular mechanisms underlying HPC/OC activa-tion has therapeutic implications for rational design of anti-fibrotic therapies.

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