• antivirals
• c-yes
• hev
• host factor
• life cycle
• viral entry
• viral pathogenesis
• yes1

• Humans
• Animals
• Rats
• Hepatocytes/virology
• Hepatocytes/metabolism
• Hepatitis E virus/physiology
• Hepatitis E virus/genetics
• Hepatitis E virus/drug effects
• Hepatitis E/drug therapy
• Hepatitis E/virology
• Proto-Oncogene Proteins c-yes/genetics
• Proto-Oncogene Proteins c-yes/metabolism
• Rats, Nude
• Disease Models, Animal
• Antiviral Agents/pharmacology
• Antiviral Agents/therapeutic use

• Appetite
• Feed intake
• Glucolipid metabolism
• Krill oil
• Soybean lecithin

• Animals
• Lecithins/pharmacology
• Lecithins/metabolism
• Perches
• Glycine max
• Leptin/metabolism
• Diet/veterinary
• Fatty Acids/metabolism
• Lipid Metabolism
• Glucose/pharmacology
• Glucose/metabolism
• RNA, Messenger/metabolism

• HBV
• PPARGC1A
• chronic hepatitis B
• clearance
• variant

• Humans
• Genotype
• Hepatitis B virus/genetics
• Hepatitis B, Chronic/genetics
• Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/genetics
• Polymorphism, Single Nucleotide
• PPAR gamma/genetics
• Transcription Factors/genetics
• Transcription Factors/metabolism

• HCV core protein
• ISX
• immune suppression
• metabolic dysregulation
• programmed death-ligand 1 (PD-L1)

• Mice
• Animals
• Carcinoma, Hepatocellular
• Hepatitis C, Chronic/metabolism
• Hepatitis C, Chronic/pathology
• B7-H1 Antigen/metabolism
• Liver Neoplasms
• Hepatitis C/metabolism
• Mice, Transgenic
• Disease Progression

• KMUH106-6R33 Kaohsiung Medical University Hospital
• KMUH107-7R46 Kaohsiung Medical University Hospital
• KMUH107-7R34 Kaohsiung Medical University Hospital
• MOST108-2314-B-037-065-MY3 Ministry of Science and Technology, Taiwan
• 109-2326-B-003-001-MY3 Ministry of Science and Technology, Taiwan
• 110-2314-B-037-072-MY3 Ministry of Science and Technology, Taiwan
• 111-2320-B-037-031 Ministry of Science and Technology, Taiwan
• KMU-DK108012 Kaohsiung Medical University
• DK(A)112002 Kaohsiung Medical University
• EO-111-PP10-014 National Health Research Institutes
• NSTC-111-2320-B-400 -026 National Science and Technology Council, Taiwan
• KQTD20170331145453160 Shenzhen Science and Technology Peacock Team Project
• Kaohsiung Medical University Hospital
• Ministry of Science and Technology, Taiwan
• Kaohsiung Medical University
• National Health Research Institutes

• antiviral agents
• lipid metabolism
• oncogenic viruses
• viral diseases

• 314730_166609 Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung
• 320030_200530 Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung

• Immunometabolism
• Inflammation
• Lipid droplets
• Lipid metabolism
• Neuroinfection
• Zika virus

Hepatitis C virus (HCV) relies on cellular lipid metabolism for its replication, and actively modulates lipogenesis and lipid trafficking in infected hepatocytes. This translates into an intracellular accumulation of triglycerides leading to liver steatosis, cirrhosis and hepatocellular carcinoma, which are hallmarks of HCV pathogenesis. While the interaction of HCV with hepatocyte metabolic pathways is patent, how viral proteins are able to redirect central carbon metabolism towards lipogenesis is unclear. Here, we report that the HCV protein NS5A activates the glucokinase (GCK) isoenzyme of hexokinases through its D2 domain (NS5A-D2). GCK is the first rate-limiting enzyme of glycolysis in normal hepatocytes whose expression is replaced by the hexokinase 2 (HK2) isoenzyme in hepatocellular carcinoma cell lines. We took advantage of a unique cellular model specifically engineered to re-express GCK instead of HK2 in the Huh7 cell line to evaluate the consequences of NS5A-D2 expression on central carbon and lipid metabolism. NS5A-D2 increased glucose consumption but decreased glycogen storage. This was accompanied by an altered mitochondrial respiration, an accumulation of intracellular triglycerides and an increased production of very-low density lipoproteins. Altogether, our results show that NS5A-D2 can reprogram central carbon metabolism towards a more energetic and glycolytic phenotype compatible with HCV needs for replication.

• NS5A
• central carbon metabolism
• glucokinase
• glycolysis
• hepatitis C virus
• hepatocyte
• human lipoprotein
• lipogenesis

Hepatitis C virus (HCV) infection induces the degradation and decreases the secretion of apolipoprotein B (ApoB). Impaired production and secretion of ApoB-containing lipoprotein is associated with an increase in hepatic steatosis. Therefore, HCV infection-induced degradation of ApoB may contribute to hepatic steatosis and decreased lipoprotein secretion, but the mechanism of HCV infection-induced ApoB degradation has not been completely elucidated. In this study, we found that the ApoB level in HCV-infected cells was regulated by proteasome-associated degradation but not autophagic degradation. ApoB was degraded by the 20S proteasome in a ubiquitin-independent manner. HCV induced the oxidation of ApoB via oxidative stress, and oxidized ApoB was recognized by the PSMA5 and PSMA6 subunits of the 20S proteasome for degradation. Further study showed that ApoB was degraded at endoplasmic reticulum (ER)-associated lipid droplets (LDs) and that the retrotranslocation and degradation of ApoB required Derlin-1 but not gp78 or p97. Moreover, we found that knockdown of ApoB before infection increased the cellular lipid content and enhanced HCV assembly. Overexpression of ApoB-50 inhibited lipid accumulation and repressed viral assembly in HCV-infected cells. Our study reveals a novel mechanism of ApoB degradation and lipid accumulation during HCV infection and might suggest new therapeutic strategies for hepatic steatosis.

Hepatitis C virus (HCV) infection induces the degradation of apolipoprotein B (ApoB), which is the primary apolipoprotein in low-density lipoprotein (LDL) and very low-density lipoprotein (VLDL). Impaired production and secretion of ApoB-containing lipoprotein is associated with an increase in hepatic steatosis. Thus, ApoB degradation might contribute to HCV infection-induced fatty liver. Here, we found that ApoB was not degraded through endoplasmic reticulum-associated degradation (ERAD) or autophagy, as reported previously. Instead, HCV infection induced ApoB oxidation through oxidative stress, and oxidatively damaged ApoB could be recognized and directly degraded by the 20S proteasome. We also found that ApoB was retrotranslocated from the endoplasmic reticulum (ER) to lipid droplets (LDs) for degradation. Through overexpression of ApoB-50, which can mediate the assembly and secretion of LDL and VLDL, we confirmed that ApoB degradation contributed to hepatocellular lipid accumulation induced by HCV infection. Additionally, expression of ApoB-50 impaired HCV production due to the observed decrease in lipid accumulation. In this study, we identified new mechanisms of ApoB degradation and HCV-induced lipid accumulation, and our findings might facilitate the development of novel therapeutic strategies for HCV infection-induced fatty liver.

• Apolipoproteins B/metabolism
• Cell Line
• Fatty Liver/metabolism
• Fatty Liver/virology
• Hepacivirus/metabolism
• Hepatitis C/metabolism
• Hepatitis C/pathology
• Humans
• Oxidation-Reduction
• Oxidative Stress/physiology
• Proteasome Endopeptidase Complex/metabolism

• National Natural Science Foundation of China
• National Key Plan for Scientific Research and Development of China
• CAMS Innovation Fund for Medical Science

• CMV
• COVID-19
• Infection
• Inflammation
• Influenza A
• Insulin
• Insulin resistance
• LCMV
• Obesity
• Type 2 diabetes mellitus

• PPARG
• berberine
• in vitro maturation
• lipid metabolism
• porcine oocyte

• FAdV-4
• LXR-α
• activation
• lipogenesis
• steatosis
• viral replication

• Antidiabetic drugs
• COVID-19
• Corona virus
• Diabetes
• Diabetes mellitus type 2
• Immune defects
• Immune system
• Immunometabolism
• Infection
• Insulin resistance
• T2D
• Viral infection

• Comorbidity
• Diabetes Mellitus, Type 2/epidemiology
• Global Health
• Humans
• Incidence
• Risk Factors
• Virus Diseases/epidemiology

Hepatocellular carcinoma (HCC) is the third leading cause of cancer deaths worldwide. Abnormal de novo lipogenesis is reported to be involved in hepatocarcinogenesis. In current study, de novo lipogenesis and its association with patient survival rate were investigated in human HCC samples induced by hepatitis B virus (HBV), hepatitis C virus (HCV), or nonviral factors. Hepatic mRNA and protein levels of lipogenic transcription factors and lipid synthesis enzymes were examined by realtime‐PCR (RT‐PCR) and western blot. Association of gene expression and patient survival was analyzed using The Cancer Genome Atlas (TCGA) data. Lipogenic pathway regulators such as AKT2, SREBP1c, PPARγ, and lipogenic enzymes such as ACC and FAS were increased in human HCC when compared with control livers. Notably, a more robust increase in de novo lipogenesis was observed in HCV‐HCC when compared to HBV‐HCC and nonviral HCC. High FAS and ACC expression correlated with poor overall survival (OS) in HCV‐HCC. High expression of lipogenesis gene panel significantly correlated with poor OS in HCV‐HCC, but not in HBV‐HCC or nonviral HCC. In sum, de novo lipogenesis is stimulated dramatically in human HCC especially in HCV‐HCC.

• HCV‐HCC
• de novo lipogenesis
• human hepatocellular carcinoma

The correlation between hepatitis B virus (HBV) infection and metabolic syndrome (MetS) remains to be clarified. In this study, we explored this association in a large population in Southwest China. This was a cross-sectional study, with pooled adult health data. Multivariate logistic regression analysis, controlling for age, sex, HBV status, alanine aminotransferase, and fatty liver, was used to identify predictor(s) of MetS. Of the 96,175 participants, positive HBV was identified in 7984 (8.30%) and MetS in 12,092 (12.57%). The MetS prevalence was lower among HBV positive than negative individuals (11.64% versus 12.66%, P < 0.001). The adjusted odds (aOR) of positive HBV among individuals with MetS was 0.841 (95% confidence interval (CI), 0.771–0.916) in men and 0.834 (95% CI, 0.672–0.925) in women. Elevated triglyceride level, a component of MetS, was inversely associated with HBV status in both men and women: aOR, 0.551 (95% CI, 0.514–0.590) and 0.683 (95% CI, 0.605–0.769), respectively. Among HBV positive individuals, liver cirrhosis was more common among those with than without MetS (4.83% versus 2.93%, respectively; P = 0.002). HBsAg-seropositive are inversely associated with MetS, especially elevated triglycerides. Liver cirrhosis was more common among HBV infection patients with MetS.

Hepatocellular carcinoma (HCC) is a primary malignancy of the liver with a high worldwide prevalence and poor prognosis. Researches are urgently needed on its molecular pathogenesis and biological characteristics. Metabolic reprogramming for adaptation to the tumour microenvironment (TME) has been recognized as a hallmark of cancer. Dysregulation of lipid metabolism especially fatty acid (FA) metabolism, which involved in the alternations of the expression and activity of lipid‐metabolizing enzymes, is a hotspot in recent study, and it may be involved in HCC development and progression. Meanwhile, immune cells are also known as key players in the HCC microenvironment and show complicated crosstalk with cancer cells. Emerging evidence has shown that the functions of immune cells in TME are closely related to abnormal lipid metabolism. In this review, we summarize the recent findings of lipid metabolic reprogramming in TME and relate these findings to HCC progression. Our understanding of dysregulated lipid metabolism and associated signalling pathways may suggest a novel strategy to treat HCC by reprogramming cell lipid metabolism or modulating TME.

• fatty acid oxidation
• fatty acid synthesis
• hepatocellular carcinoma
• local immune status
• metabolic reprogramming
• tumour microenvironment

Insulin resistance and diabetes are both associated with chronic hepatitis C virus (HCV) infection, and the glucagon-like peptide-1(GLP-1) receptor agonist, liraglutide, is a common therapy for diabetes. Our aim was to investigate whether liraglutide treatment can inhibit HCV replication. A cell culture-produced HCV infectious system was generated by transfection of in vitro-transcribed genomic JFH-1 ribonucleic acid (RNA) into Huh-7.5 cells. Total RNA samples were extracted to determine the efficiency of HCV replication. The Ava5 cells were treated with liraglutide and cell viability was calculated. A Western blot analysis of the protein expression was performed. The immunoreactive blot signals were also detected. Liraglutide activated GLP-1 receptors in the HCV infectious system, and inhibited subgenomic HCV RNA replication in the HuH-7.5 cells. The Western blot analysis revealed both HCV protein and replicon RNA were reduced after treatment with liraglutide in a dose-dependent manner. Liraglutide decreased the cell viability of HCV RNA at an optimum concentration of 120 μg/mL, activated the 5′ adenosine monophosphate-activated protein kinase (AMPK) and the phosphorylated- transducer of regulated cyclic adenosine monophosphate (CAMP) response element-binding protein 2 (TORC2), thereby decreasing the cell viability of phosphoenolpyruvate carboxykinase (PEPCK) and G6pase RNA Therefore, we conclude that liraglutide can inhibit HCV replication via an AMPK/TORC2-dependent pathway.

• AMPK
• GLP-1
• diabetes mellitus
• hepatitis C virus
• liraglutide

• diabetes
• glucose
• infection
• insulin resistance
• metabolic disease

• Inflammation
• Lipogenesis
• Nutritional intervention
• Steatosis
• β-oxidation

• 2A
• SREBP1a
• coxsackievirus B3
• lipid accumulation
• virus replication

• Binding Sites
• Coxsackievirus Infections/genetics
• Coxsackievirus Infections/metabolism
• Coxsackievirus Infections/virology
• Enterovirus B, Human/metabolism
• Enterovirus B, Human/pathogenicity
• HeLa Cells
• Humans
• Lipid Metabolism
• MAP Kinase Signaling System
• Promoter Regions, Genetic
• Sp1 Transcription Factor/metabolism
• Sterol Regulatory Element Binding Protein 1/chemistry
• Sterol Regulatory Element Binding Protein 1/genetics
• Sterol Regulatory Element Binding Protein 1/metabolism
• Transcriptional Activation
• Up-Regulation
• Viral Nonstructural Proteins/metabolism
• Virus Replication

• National Natural Science Foundation of China (NSFC)
• Chongqing Science and Technology Commission (CSTC)

Sterol regulatory element-binding protein-1c (SREBP1c) plays an important role in triglyceride (TG) homeostasis. Although our previous study showed that hepatitis C virus core-binding protein 6 (HCBP6) regulates SREBP1c expression to maintain intracellular TG homeostasis, the mechanism underlying this regulation is unclear. In the present study, we found that HCBP6 increased intracellular TG levels by upregulating SREBP1c expression. HCBP6 increased SREBP1c transcription by directly binding to the SREBP1c promoter (at the −139- to +359-bp region). Moreover, we observed that HCBP6 interacted with C/EBPβ-binding site in the SREBP1c promoter both in vitro and in vivo. These results indicate that HCBP6 upregulates human SREBP1c expression by binding to the C/EBPβ-binding site in the SREBP1c promoter.

• Non-alcoholic fatty liver disease. Hepatitis C virus core-binding protein. SREBP-1c.

• Alanine Transaminase/blood
• Animals
• Aspartate Aminotransferases/blood
• Carbon Tetrachloride
• Chemical and Drug Induced Liver Injury/etiology
• Chemical and Drug Induced Liver Injury/genetics
• Chemical and Drug Induced Liver Injury/metabolism
• Chemical and Drug Induced Liver Injury/pathology
• Cholesterol/blood
• Core Binding Factors/genetics
• Core Binding Factors/metabolism
• Diet, High-Fat
• Female
• Liver/metabolism
• Liver/pathology
• Male
• Membrane Proteins/metabolism
• Mitochondrial Proteins/metabolism
• Non-alcoholic Fatty Liver Disease/etiology
• Non-alcoholic Fatty Liver Disease/genetics
• Non-alcoholic Fatty Liver Disease/metabolism
• Non-alcoholic Fatty Liver Disease/pathology
• Rats, Wistar
• Sterol Regulatory Element Binding Protein 1/genetics
• Sterol Regulatory Element Binding Protein 1/metabolism
• Triglycerides/blood

Cytoplasmic vacuolization (also called cytoplasmic vacuolation) is a well-known morphological phenomenon observed in mammalian cells after exposure to bacterial or viral pathogens as well as to various natural and artificial low-molecular-weight compounds. Vacuolization often accompanies cell death; however, its role in cell death processes remains unclear. This can be attributed to studying vacuolization at the level of morphology for many years. At the same time, new data on the molecular mechanisms of the vacuole formation and structure have become available. In addition, numerous examples of the association between vacuolization and previously unknown cell death types have been reported. Here, we review these data to make a deeper insight into the role of cytoplasmic vacuolization in cell death and survival.

• microbial toxins
• regulated cell death
• vacuolization
• viruses

• Hepatitis C
• Hypobetalipoproteinemia
• Insulin resistance
• Microsomal triglyceride transfer protein
• Steatosis
• Tumor necrosis factor

• Animals
• Cytokines/metabolism
• Diabetes Mellitus, Type 2/epidemiology
• Dyslipidemias/metabolism
• Fatty Liver/epidemiology
• Hepacivirus
• Hepatitis C, Chronic/complications
• Hepatitis C, Chronic/epidemiology
• Hepatitis C, Chronic/metabolism
• Humans
• Incretins/metabolism
• Insulin Resistance
• Insulin-Secreting Cells/virology
• Lipid Metabolism
• Mice
• Prevalence
• Risk Factors
• Signal Transduction

• lipid droplets
• lipoproteins/metabolism
• liver
• triglyceride

• Acetyl-CoA Carboxylase/antagonists & inhibitors
• Cells, Cultured
• Enzyme Inhibitors/pharmacology
• Fatty Acids/metabolism
• Hepacivirus/drug effects
• Hepacivirus/physiology
• Hepatitis C/drug therapy
• Hepatitis C/metabolism
• Hepatitis C/virology
• Hepatocytes/cytology
• Hepatocytes/drug effects
• Hepatocytes/metabolism
• Humans
• Lipogenesis/physiology
• RNA, Viral/genetics
• Virus Replication/drug effects

• R01 DK101803 NIDDK NIH HHS
• T32 AI007496 NIAID NIH HHS
• F30 DK104562 NIDDK NIH HHS
• R01 AI098126 NIAID NIH HHS
• T32 GM007055 NIGMS NIH HHS
• U19 AI066328 NIAID NIH HHS
• National Institutes of Health

• deep sequencing
• irradiation
• liver
• miRNA
• mouse

• FATTY ACID
• GENE EXPRESSION
• LIPASE/HEPATIC
• MicroRNA-122
• NUCLEAR RECEPTORS/SREBP
• TRIGLYCERIDES

The cluster of differentiation 36 (CD36) is a membrane protein related to lipid metabolism. We show that HCV infection in vitro increased CD36 expression in either surface or soluble form. HCV attachment was facilitated through a direct interaction between CD36 and HCV E1 protein, causing enhanced entry and replication. The HCV co-receptor effect of CD36 was independent of that of SR-BI. CD36 monoclonal antibodies neutralized the effect of CD36 and reduced HCV replication. CD36 inhibitor sulfo-N-succinimidyl oleate (SSO), which directly bound CD36 but not SR-BI, significantly interrupted HCV entry, and therefore inhibited HCV replication. SSO’s antiviral effect was seen only in HCV but not in other viruses. SSO in combination with known anti-HCV drugs showed additional inhibition against HCV. SSO was considerably safe in mice. Conclusively, CD36 interacts with HCV E1 and might be a co-receptor specific for HCV entry; thus, CD36 could be a potential drug target against HCV.

Diabetogenic traits in patients undergoing liver transplantation (LT) are exacerbated intraoperatively by exogenous causes, such as surgical stress, steroids, blood transfusions, and catecholamines, which lead to intraoperative hyperglycemia. In contrast to the strict glucose control performed in the intensive care unit, no systematic protocol has been developed for glucose management during LT. Intraoperative blood glucose concentrations typically exceed 200 mg/dL in LT, and extreme hyperglycemia (> 300 mg/dL) is common during the neohepatic phase. Only a few retrospective studies have examined the relationship between intraoperative hyperglycemia and post-transplant complications, with reports of infectious complications or mortality. However, no prospective studies have been conducted regarding the influence of intraoperative hyperglycemia in LT on post-transplant outcome. In addition to absolute blood glucose values, the temporal patterns in blood glucose levels during LT may serve as prognostic features. Persistent neohepatic hyperglycemia (without a decline) throughout LT is a useful indicator of early graft dysfunction. Moreover, intraoperative variability in glucose levels may predict the need for reoperation for hemorrhage after LT. Thus, there is an urgent need for guidelines for glucose control in these patients, as well as prospective studies on the impact of glucose control on various post-transplant complications. This report highlights some of the recent studies related to perioperative blood glucose management focused on LT and liver disease.

• Blood glucose
• Intraoperative
• Liver transplantation
• Outcome
• Prediction

• Biomarkers/blood
• Blood Glucose/analysis
• End Stage Liver Disease/blood
• End Stage Liver Disease/complications
• End Stage Liver Disease/mortality
• End Stage Liver Disease/surgery
• Humans
• Hyperglycemia/blood
• Hyperglycemia/diagnosis
• Hyperglycemia/etiology
• Hyperglycemia/therapy
• Hyperinsulinism/blood
• Hyperinsulinism/etiology
• Hypoglycemic Agents/therapeutic use
• Insulin Resistance
• Liver Transplantation/adverse effects
• Liver Transplantation/mortality
• Monitoring, Intraoperative/methods
• Postoperative Complications/mortality
• Postoperative Complications/therapy
• Predictive Value of Tests
• Risk Factors
• Treatment Outcome

There is controversy regarding some aspects of hepatitis C virus (HCV) infection-associated liver steatosis, and their relationship with body fat stores. It has classically been found that HCV, especially genotype 3, exerts direct metabolic effects which lead to liver steatosis. This supports the existence of a so called viral steatosis and a metabolic steatosis, which would affect HCV patients who are also obese or diabetics. In fact, several genotypes exert metabolic effects which overlap with some of those observed in the metabolic syndrome. In this review we will analyse the pathogenic pathways involved in the development of steatosis in HCV patients. Several cytokines and adipokines also become activated and are involved in “pure” steatosic effects, in addition to inflammation. They are probably responsible for the evolution of simple steatosis to steatohepatitis, making it difficult to explain why such alterations only affect a proportion of steatosic patients.

• Hepatitis C virus steatosis adiponectin
• Leptin
• Insulin resistance
• Proinflammatory cytokines
• Triglyceride synthesis
• Fatty acid oxidation

AIM: To investigate the molecular mechanism for regulation of cholesterol metabolism by hepatitis C virus (HCV) core protein in HepG2 cells.

METHODS: HCV genotype 1b core protein was cloned and expressed in HepG2 cells. The cholesterol content was determined after transfection. The expression of sterol regulatory element binding protein 2 (SREBP2) and the rate-limiting enzyme in cholesterol synthesis (HMGCR) was measured by quantitative real-time PCR and immunoblotting after transfection. The effects of core protein on the SREBP2 promoter and 3’-untranslated region were analyzed by luciferase assay. We used different target predictive algorithms, microRNA (miRNA) mimics/inhibitors, and site-directed mutation to identify a putative target of a particular miRNA.

RESULTS: HCV core protein expression in HepG2 cells increased the total intracellular cholesterol level (4.05 ± 0.17 vs 6.47 ± 0.68, P = 0.001), and this increase corresponded to an increase in SREBP2 and HMGCR mRNA levels (P = 0.009 and 0.037, respectively) and protein expression. The molecular mechanism study revealed that the HCV core protein increased the expression of SREBP2 by enhancing its promoter activity (P = 0.004). In addition, miR-185-5p expression was tightly regulated by the HCV core protein (P = 0.041). Moreover, overexpression of miR-185-5p repressed the SREBP2 mRNA level (P = 0.022) and protein expression. In contrast, inhibition of miR-185-5p caused upregulation of SREBP2 protein expression. miR-185-5p was involved in the regulation of SREBP2 expression by HCV core protein.

CONCLUSION: HCV core protein disturbs the cholesterol homeostasis in HepG2 cells via the SREBP2 pathway; miR-185-5p is involved in the regulation of SREBP2 by the core protein.

• Cholesterol
• Hepatitis C virus core protein
• miR-185-5p
• Steatosis
• Sterol response element binding proteins

• 3' Untranslated Regions
• Binding Sites
• Cholesterol/metabolism
• Gene Expression Regulation
• Hep G2 Cells
• Homeostasis
• Humans
• Hydroxymethylglutaryl CoA Reductases/metabolism
• MicroRNAs/genetics
• MicroRNAs/metabolism
• Promoter Regions, Genetic
• Sterol Regulatory Element Binding Protein 2/genetics
• Sterol Regulatory Element Binding Protein 2/metabolism
• Transfection
• Viral Core Proteins/genetics
• Viral Core Proteins/metabolism

• HCV
• directly acting antiviral agents
• genotype 3
• metabolic syndrome
• steatosis

• Adipose Triglyceride Lipase (ATGL)
• Hepatitis C Virus (HCV)
• Lipid Droplet
• Lipolysis
• Triglyceride

• Bacteria
• fungi
• nuclear receptor
• parasites
• viruses

• Adult
• Animals
• Antiviral Agents/therapeutic use
• Drug Therapy, Combination
• Female
• Follow-Up Studies
• HIV Infections/complications
• Hepacivirus/isolation & purification
• Hepatitis C, Chronic/complications
• Hepatitis C, Chronic/drug therapy
• Humans
• Interferon-alpha/therapeutic use
• Interferons
• Interleukins/genetics
• Male
• Middle Aged
• PPAR gamma/genetics
• Polymorphism, Single Nucleotide
• RNA, Viral/blood
• Retrospective Studies
• Ribavirin/therapeutic use
• Time
• Treatment Outcome
• Viral Load

• Cancer
• Free radicals
• HCV
• Inflammation
• NADPH oxidase
• Reactive oxygen species

• Animals
• Carcinoma, Hepatocellular/metabolism
• Hepatitis C, Chronic/complications
• Hepatitis C, Chronic/metabolism
• Humans
• Liver Neoplasms/metabolism
• NADPH Oxidases/metabolism
• Oxidative Stress/physiology

• R01 CA158271 NCI NIH HHS
• R01CA158271 NCI NIH HHS

• Apolipoproteins E/biosynthesis
• Cell Line, Tumor
• Gene Expression Regulation
• Gene Silencing
• Hepacivirus/physiology
• Hepatocytes/virology
• Humans
• Nuclear Receptor Subfamily 4, Group A, Member 1/antagonists & inhibitors
• Nuclear Receptor Subfamily 4, Group A, Member 1/metabolism
• Receptors, Virus/biosynthesis
• Virus Internalization

• Genetics
• Hepatitis C virus
• Immune response
• Lipids
• Metabolism

• Animals
• Antiviral Agents/therapeutic use
• Disease Progression
• Fatty Liver/immunology
• Hepacivirus
• Hepatitis C/genetics
• Hepatitis C/immunology
• Humans
• Hypercholesterolemia/complications
• Hypercholesterolemia/virology
• Immunity, Innate
• Lipid Metabolism
• Mexico
• Obesity/complications
• Risk Factors
• United States

• Animals
• Carcinoma, Hepatocellular/etiology
• Cell Transformation, Neoplastic/pathology
• Hepacivirus/pathogenicity
• Hepatitis C/complications
• Humans
• Liver Neoplasms/etiology
• Mice

Hepatitis C virus (HCV) replication is dependent on the formation of specialized membrane structures; however, the host factor requirements for the formation of these HCV complexes remain unclear. Herein, we demonstrate that inhibition of stearoyl-CoA desaturase 1 (SCD-1) halts the biosynthesis of unsaturated fatty acids, such as oleic acid, and negatively modulates HCV replication. Unsaturated fatty acids play key roles in membrane curvature and fluidity. Mechanistically, we demonstrate that SCD-1 inhibition disrupts the integrity of membranous HCV replication complexes and renders HCV RNA susceptible to nuclease-mediated degradation. Our work establishes a novel function for unsaturated fatty acids in HCV replication.

Hepatitis C virus (HCV) infection disrupts the normal metabolism processes, but is also influenced by several of the host’s metabolic factors. An obvious and significantly detrimental pathophysiological feature of HCV infection is insulin resistance in hepatic and peripheral tissues. Substantial research efforts have been put forth recently to elucidate the molecular mechanism of HCV-induced insulin resistance, and several cytokines, such as tumor necrosis factor-α, have been identified as important contributors to the development of insulin resistance in the distant peripheral tissues of HCV-infected patients and animal models. The demonstrated etiologies of HCV-induced whole-body insulin resistance include oxidative stress, lipid metabolism abnormalities, hepatic steatosis and iron overload. In addition, myriad effects of this condition have been characterized, including glucose intolerance, resistance to antiviral therapy, progression of hepatic fibrosis, development of hepatocellular carcinoma, and general decrease in quality of life. Metabolic-related conditions and disorders, such as visceral obesity and diabetes mellitus, have been shown to synergistically enhance HCV-induced metabolic disturbance, and are associated with worse prognosis. Yet, the molecular interactions between HCV-induced metabolic disturbance and host-associated metabolic factors remain largely unknown. The diet and lifestyle recommendations for chronic hepatitis C are basically the same as those for obesity, diabetes, and metabolic syndrome. Specifically, patients are suggested to restrict their dietary iron intake, abstain from alcohol and tobacco, and increase their intake of green tea and coffee (to attain the beneficial effects of caffeine and polyphenols). While successful clinical management of HCV-infected patients with metabolic disorders has also been achieved with some anti-diabetic (i.e., metformin) and anti-lipid (i.e., statins) medications, it is recommended that sulfonylurea and insulin be avoided.

• Hepatitis C virus
• Insulin resistance
• Diabetes
• Lipid metabolism abnormality
• Hepatic steatosis
• Iron overload
• Oxidative stress
• Visceral obesity

• Animals
• Diet Therapy
• Fatty Liver/metabolism
• Glucose/metabolism
• Hepatitis C/metabolism
• Hepatitis C/therapy
• Humans
• Hypoglycemic Agents/therapeutic use
• Hypolipidemic Agents/therapeutic use
• Insulin Resistance
• Iron/metabolism
• Lipid Metabolism
• Oxidative Stress

• cell signaling pathways
• hepatitis C virus
• hepcidin
• iron
• lipid metabolism

Approximately 170 million people worldwide are chronically infected with hepatitis C virus (HCV). Chronic HCV infection is the leading cause for the development of liver fibrosis, cirrhosis, hepatocellular carcinoma (HCC) and is the primary cause for liver transplantation in the western world. Insulin resistance is one of the pathological features in patients with HCV infection and often leads to development of type II diabetes. Insulin resistance plays an important role in the development of various complications associated with HCV infection. Recent evidence indicates that HCV associated insulin resistance may result in hepatic fibrosis, steatosis, HCC and resistance to anti-viral treatment. Thus, HCV associated insulin resistance is a therapeutic target at any stage of HCV infection. HCV modulates normal cellular gene expression and interferes with the insulin signaling pathway. Various mechanisms have been proposed in regard to HCV mediated insulin resistance, involving up regulation of inflammatory cytokines, like tumor necrosis factor-α, phosphorylation of insulin-receptor substrate-1, Akt, up-regulation of gluconeogenic genes like glucose 6 phosphatase, phosphoenolpyruvate carboxykinase 2, and accumulation of lipid droplets. In this review, we summarize the available information on how HCV infection interferes with insulin signaling pathways resulting in insulin resistance.

• Hepatitis C virus
• Insulin resistance
• Insulin receptor substrate 1
• Protein kinase B
• mammalian target of rapamycin/S6K1
• Suppressor of cytokine signaling 3
• Glucose transporter-4
• Lipid metabolism
• Anti-viral therapy

• NAFLD
• cholesterol
• hepatitis C
• lipid metabolism
• statins