Hepatitis C Virus, Insulin Resistance, and Steatosis

Abstract

Hepatitis C virus (HCV) is one of the main causes of liver disease worldwide. Liver steatosis is a common finding in many hepatic and extrahepatic disorders, the most common being metabolic syndrome (MS). Over time, it has been shown that the frequent coexistence of these two conditions is not coincidental, since many epidemiological, clinical, and experimental studies have indicated HCV to be strongly associated with liver steatosis and numerous metabolic derangements. Here, we present an overview of publications that provide clinical evidence of the metabolic effects of HCV and summarize the available data on the pathogenetic mechanisms of this association. It has been shown that HCV infection can induce insulin resistance (IR) in the liver and peripheral tissues through multiple mechanisms. Substantial research has suggested that HCV interferes with insulin signaling both directly and indirectly, inducing the production of several proinflammatory cytokines. HCV replication, assembly, and release from hepatocytes require close interactions with lipid droplets and host lipoproteins. This modulation of lipid metabolism in host cells can induce hepatic steatosis, which is more pronounced in patients with HCV genotype 3. The risk of steatosis depends on several viral factors (including genotype, viral load, and gene mutations) and host features (visceral obesity, type 2 diabetes mellitus, genetic predisposition, medication use, and alcohol consumption). HCV-related IR and steatosis have been shown to have a remarkable clinical impact on the prognosis of HCV infection and quality of life, due to their association with resistance to antiviral therapy, progression of hepatic fibrosis, and development of hepatocellular carcinoma. Finally, HCV-induced IR, oxidative stress, and changes in lipid and iron metabolism lead to glucose intolerance, arterial hypertension, hyperuricemia, and atherosclerosis, resulting in increased cardiovascular mortality.

Metabolic signaling functions of ER–mitochondria contact sites: role in metabolic diseases

“…This is the case of neurodegenerative diseases, such as Alzheimer's disease (AD) (Kandimalla et al 2016), viral infections (Kralj et al 2016), Wolfram syndrome (Boutzios et al 2011) or some cancers (Klil-Drori et al 2016). Interestingly, ERmitochondria miscommunication has recently been suggested or reported in these pathologies.…”

Metabolic Syndrome and Genotype 1 Virus C Compensated Liver Cirrhosis in the Era of Directly Acting Antiviral Therapy

“…In the hepatocyte, HCV interferes with the lipid metabolism of the host to replicate and assemble leading to hepatic steatosis. The main mechanisms through which HCV leads to accumulation of triglycerides in the hepatocyte are the activation of lipogenesis, its impact on mitochondrial lipid oxidation, the lowering of microsomal triglyceride transfer protein activity, and the reduced activity of peroxisome proliferator activating receptor (PPAR) (4). The release of the virus from hepatocytes occurs by means of the very low-density lipoprotein (VLDL) (25).…”

“…ment of hepatic insulin-resistance in patients with HCV, both through a direct viral effect and through inflammatory cytokines: the inhibition of insulin receptor substrate (IRS), and the activation of suppressor of cytokine sing-align (SOCS) with inhibition of phosphatidylinositol 3 kinase-transducer, which has a key role in insulin metabolism (4). As far as the lipid metabolism is concerned, HCV relies on the host lipid metabolism to enter the hepatocytes and replicate, consequently impacting on the lipid metabolism itself (5).…”

PI3K/SHIP2/PTEN pathway in cell polarity and hepatitis C virus pathogenesis

“…Other studies have also shown that HCV infection can cause insulin resistance by the phosphorylation of IRS-1 at a serine residue (Ser307) followed by a decreased phosphorylation of Akt Thr(308), Fox01 Ser(256) and GSK3β Ser(9), downstream players in the insulin signaling pathway[72,73]. These data raise the question whether insulin resistance is the cause of liver steatosis in patients with chronic HCV infection, or the consequence of viral molecular expression.…”