Pathogenesis,of,fatty,liver,diseases,and,hepatocellular,carcinoma☆

The prevalence of fatty liver diseases has increased rapidly in recent years to about 25%worldwide.Fatty liver diseases are multifaceted in pathogenesis,disease phenotype,and mechanism.It is important to understand disease pathogenesis and mechanism in order to develop effective and safe drug therapy for treating fatty liver diseases.Alcoholic fatty liver disease(AFLD,or alcohol associated liver disease)and viral hepatitis have been the major causes of liver transplant,liver cancer,and death.Chronic and acute alcohol consumption causes hepatic steatosis,which can progress to alcoholic steatohepatitis (ASH),fibrosis,cirrhosis,and hepatocellular carcinoma(HCC).Non-alcoholic fatty liver disease(NAFLD,or metabolic associated liver disease) is a spectrum of disease conditions from simple steatosis to non-alcoholic steatohepatitis (NASH),which progresses to fibrosis and cirrhosis.In the last two decades,NAFLD has exceeded AFLD and viral hepatitis as the number one cause of liver transplant.Obesity,insulin resistance,and type 2 diabetes are major contributors to the pathogenesis of NAFLD.The mechanism of progression from simple steatosis to steatohepatitis is not well understood.The increase of ASH and NASH also increases the incidence of HCC and other end stage liver diseases.Identification of biomarkers is important for early diagnosis of ASH and NASH.The therapeutic strategy for ASH and NASH is to prevent or reverse inflammation,cell death,and fibrosis progression.Currently there is no US Food and Drug Administration(FDA)approved drug therapy for treating NASH and ASH fibrosis.

This special issue covers emerging areas of research in fatty liver diseases:liver metabolism,mechanism of liver disease progression,biomarker and diagnosis of HCC,and therapy for fatty liver diseases and HCC.

Liver metabolism:maintaining metabolic homeostasis is important for normal cellular function.The liver is an important metabolic organ that plays a critical role in maintaining whole body metabolic homeostasis.Chen1provided a review of the role of iron metabolism in NAFLD.Iron is essential for cellular function and metabolism.Iron overload can cause liver injury due to increased reactive oxygen species.This review describes the molecular mechanism of iron homeostasis in the liver and the mechanisms by which iron overload causes liver injury,insulin resistance and NASH fibrosis,cirrhosis and HCC,and therapeutic strategies targeting iron metabolism for NAFLD treatment.

Sex differences in the prevalence to NAFLD and NASH have been reported.Female sex has a lower prevalence than male sex in dietinduced obesity and NAFLD.However,the prevalence of NAFLD in women has increased in recent years,especially among postmenopausal females.Ferrellet al.2studied the role of bile acid activated Takeda G protein-coupled receptor 5 (TGR5) in high fat,fructose,and sucrose diet-induced NAFLD mouse model.The study found femaleTgr5-/-mice were more resistant to developing diet-induced obesity and glucose intolerance despite increased expression of genes in lipogenesis and reduced expression of genes in bile acid synthesis and hepatic inflammation and fibrosis markers.They found that serotonin signaling in the liver was altered inTgr5-/-mice.Serotonin signaling has been implicated in liver fibrosis and inhibition of serotonin receptors may be protective from liver fibrosis.Altered serotonin metabolism inTgr5-/-mice may reduce fibrogenic serotonin receptor signaling and protect against dietinduced fibrosis inTgr5-/-mice.

Increasing evidence has implicated crosstalk of liver and adipose tissue in the pathogenesis of alcohol-associated liver disease(ALD).Rodriguezet al.3studied acute alcohol drinking on liver steatosis and adipose tissue lipolysis and atrophy.This study used liver and adipose tissue specific mechanistic target of rapamycin (mTOR)knockout mouse models and regulatory-associated protein of mTOR (Rptor) knockout mouse models to study mTOR signaling in lipid metabolism and inflammation in liver and adipose tissues.This study showed that adipocyte but not hepatocyte ablation ofMtorpathway contributed to acute alcohol-induced liver injury,which suggested the critical role of adipocyte mTOR in regulating the adipose-liver crosstalk in ALD.

Mechanism of liver disease progression:the mechanism of ASH and NASH fibrosis progression is complex involving many pathogenic factors and metabolic and signaling pathways.Mageeet al.4performed detailed analysis of metabolic phenotypes of mice fed a high fat,high cholesterol,and high fructose diet for 1-9 months for NASH development.They performed RNA sequencing analysis of the hepatic transcriptome signatures during transition from simple steatosis to borderline steatohepatitis.This study identified potential biomarkers for diagnosis of NASH.

Cytochrome P450 (CYP) enzymes are responsible for metabolism of drugs,carcinogens,and endogenous compounds.Drugdrug interaction can cause liver injury and liver failure.Gancao is a widely used herbal supplement that may cause herb-drug interaction by inducing CYP3A4,a predominate drug metabolizing CYP enzyme in human liver.Chenget al.5studied the phytochemicals in Gancao(licorice)and identified that glycyrrhetinic acid activated pregnane X receptor (PXR) to induce CYP3A4 in humanized PXR mice,which provided a novel insight into the mechanisms of Gancao-related herb-drug interaction.

Biomarker and diagnosis of HCC.Yanget al.6analyzed the expression of a DNA glycosylase called “MUTYH”,which plays a role in oxidative DNA damage repair and is highly expressed in HCC patients.These authors performed analysis of the database collected from The Cancer Genome Atlas (TCGA) for analysis of MUTYH in HCC.Several signatures in immune cells were identified as prognostic biomarkers for HCC.

Wanget al.7developed a model using reduction in serum total bilirubin levels to predict the effectiveness of percutaneous transhepatic biliary drainage in hepatitis C virus(HCV)infected HCC patients.This model may be useful for informed clinical decision making for performing this procedure on HCC patients.

Therapy for fatty liver diseases and HCC:several drugs targeting the bile acid signaling pathways have been investigated in clinical trials as potential NASH therapies.Matyeet al.8studied the effect of combined apical sodium-dependent bile acid transporter(ASBT)inhibitor and farnesoid X receptor(FXR)agonist obeticholic acid treatment in high fat,high cholesterol,and high fructose dietinduced NASH mouse model.This study showed neither single therapy nor combined therapy reduced hepatic steatosis,but all three treatments reduced hepatic inflammation and fibrosis to a similar extent.Thus,the combined therapy did not provide improved efficacy against NASH and liver fibrosis than the single therapy,partly due to moderate effect on reduction of total bile acid pool.In contrast,the same group recently reported that combining ASBT inhibitor with fibroblast growth factor 15(FGF15) overexpression markedly reduced total bile acid pool and dietary lipid absorption,resulting in improved obesity and NASH fibrosis in the same NASH mouse model.9

Zhanget al.10reported a population based cross-sectional study of the prevalence,diagnosis,treatment,and associated factors of hepatitis C in the United States from 1999 to 2018.HCV infection is a major cause of hepatic fibrosis,cirrhosis,and HCC worldwide.This study determined the prevalence of HCV-RNA positive and HCV genotypes in different ages and sexes in the population studied.

Authors’ contributions

J.Y.L.Chiang wrote the manuscript.T.Li edited the manuscript.

Declaration of competing interest

The authors declare that they have no conflict of interest.

Acknowledgements

This manuscript was supported by the USA National Institutes of Health (NIH) grants DK44442 and DK58379 (J.Y.L.Chiang) and 1R01DK131064 and 1R01 DK117965 (T.Li) .