Metabolic alterations and hepatitis C: From bench to bedside

Abstract

In addition to causing cirrhosis and hepatocellular carcinoma, hepatitis C virus (HCV) is thought to cause hypolipidemia, hepatic steatosis, insulin resistance, metabolic syndrome, and diabetes. The viral life cycle of HCV depends on cholesterol metabolism in host cells. HCV core protein and nonstructural protein 5A perturb crucial lipid and glucose pathways, such as the sterol regulatory element-binding protein pathway and the protein kinase B/mammalian target of rapamycin/S6 kinase 1 pathway. Although several lines of transgenic mice expressing core or full HCV proteins exhibit hepatic steatosis and/or dyslipidemia, whether they completely reflect the metabolic alterations in humans with HCV infection remains unknown. Many cross-sectional studies have demonstrated increased prevalences of metabolic alterations and cardiovascular events in patients with chronic hepatitis C (CHC); however, conflicting results exist, primarily due to unavoidable individual variations. Utilizing anti-HCV therapy, most longitudinal cohort studies of CHC patients have demonstrated the favorable effects of viral clearance in attenuating metabolic alterations and cardiovascular risks. To determine the risks of HCV-associated metabolic alterations and associated complications in patients with CHC, it is necessary to adjust for crucial confounders, such as HCV genotype and host baseline glucose metabolism, for a long follow-up period after anti-HCV treatment. Adipose tissue is an important endocrine organ due to its release of adipocytokines, which regulate lipid and glucose metabolism. However, most data on HCV infection and adipocytokine alteration are inconclusive. A comprehensive overview of HCV-associated metabolic and adipocytokine alterations, from bench to bedside, is presented in this topic highlight.

Keywords: Cardiovascular; Core; Glucose; Hepatitis C virus; Lipid; Nonstructural protein 5 A; Transgenic mice.

Figure 1

Diagram of the hepatitis C viral genome. Hepatitis C virus is a single-stranded RNA virus, and its genomic organization shows highly conserved 5’ and 3’ nonstructural proteins. UTR: Untranslated region; C: Core protein; E1 and E2: Envelope glycoprotein 1 and 2; NS: Nonstructural protein.

Figure 2

Life cycle of hepatitis C virus in the hepatocyte. Hepatitis C virus (HCV) LVPs enter hepatocytes via receptor-mediated endocytosis. Released viral RNA is translated at the endoplasmic reticulum (ER), producing a single polyprotein precursor that is cleaved by host and viral proteases. The viral NS proteins (e.g., NS5A protein) form RNA replication complexes in lipid rafts, where positive-strand RNA is replicated via a negative-strand intermediate. Newly synthesized positive-strand RNA is encapsidated by the HCV core protein in close proximity to LDs, and envelope glycoproteins are acquired through budding into the ER lumen. LVPs mature in the ER through interactions with lipoproteins and exit the cell via the cellular Golgi apparatus. LD: Lipid droplet; LVP: Lipoviral particle; Golgi: Golgi apparatus.

Figure 3

Hepatitis C virus-associated metabolic alterations in the hepatocyte, data from bench studies. SREBP: Sterol regulatory element-binding proteins; PPAR: Peroxisome proliferator-activated receptors; Glu: Glucose; Glut: Glucose transporter; ER: Endoplasmic reticulum; SRE: SREBP response element; FA: Fatty acid; PPRE: PPAR response element; PI3K: Phosphatidylinositide 3-kinase; Akt: Protein kinase B: Fox: Transcription factor forkhead box; PEPCK: Phosphoenolpyruvate carboxykinase; G6Pase: Glucose 6-phosphatase; IR: Insulin receptor; IRS: Insulin receptor sustrate; NS5A: HCV nonstructural protein 5 A; TG: Triglyceride; ApoB: Apoliporptoein B; MTTP: Microsomal triglyceride transfer protein; VLDL: Very low-density lipoprotein-cholesterol; SOCS: Suppressor of cytokine signaling proteins; mTOR: Mammalian target of rapamycin; TNF: Tumor necrosis factor; TNFR: Tumor necrosis factor receptor; LD: Lipid droplet.

Figure 4

Hepatitis C virus-associated metabolic alterations and cardiovascular events, data from human studies. CA: Carotid atherosclerosis; IMT: Intima-media thickness; IHD: Ischemic heart disease; CHF: Congestive heart failure; FL: Fatty liver; H/T: Hypertension; WC: Waist circumference; IR: Insulin resistance; DM: Diabetes; CKD: Chronic kidney disease.