Investigation of the role of SREBP-1c in the pathogenesis of HCV-related steatosis

• Published in: Journal of hepatology Vol. 49; no. 6; pp. 1046 - 1054
• Main Authors: McPherson, Stuart, Jonsson, Julie R., Barrie, Helen D., O’Rourke, Peter, Clouston, Andrew D., Powell, Elizabeth E.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.12.2008
• Subjects: Adult; Carrier Proteins - genetics; de novo lipogenesis; Fatty acid synthase; Fatty Acid Synthases - genetics; Fatty Liver - etiology; Fatty Liver - genetics; Fatty Liver - virology; Female; Gastroenterology and Hepatology; Gene Expression; Glycerol-3-phosphate acyltransferase; Glycerol-3-Phosphate O-Acyltransferase - genetics; Hepatitis C, Chronic - genetics; Hepatitis C, Chronic - pathology; Humans; Immunohistochemistry; Insulin resistance; Insulin Resistance - genetics; Lipogenesis - genetics; Male; Microsomal triglyceride transfer protein; RNA, Messenger - metabolism; Sterol Regulatory Element Binding Protein 1 - genetics; Sterol Regulatory Element Binding Protein 1 - metabolism; ACC; NAFLD; SREBP; Glycerol-3-phosphate acyltransferase; Microsomal triglyceride transfer protein; de novo lipogenesis; NASH; HuPO; ChREBP; NDL; FAS; AMPK; Insulin resistance; HCV; HOMA; qPCR; Fatty acid synthase; HBV; GPAT; GAPDH; BMI; non-alcoholic fatty liver disease; hepatitis B virus; AMP-activated protein kinase; semi-quantitative real-time polymerase chain reaction; hepatitis C virus; human acidic ribosomal protein; glyceraldehyde-3-phosphate dehydrogenase; non-diseased liver; sterol regulatory element binding protein; body mass index; glycerol-3-phosphate acyltransferase; acetyl CoA carboxylase; carbohydrate-responsive element binding protein; fatty acid synthase; homeostasis model of assessment; non-alcoholic steatohepatitis
• ISSN: 0168-8278; 1600-0641
• DOI: 10.1016/j.jhep.2008.06.022

Increased expression of sterol regulatory element binding protein (SREBP)-1c, a transcription factor regulating lipogenesis, has been reported in HCV core protein-transfected hepatocytes. Our aim was to investigate the role of SREBP-1c in the pathogenesis of HCV-related steatosis. One hundred and twenty-four patients with HCV and 13 subjects with histologically normal liver (NDL) were studied. The mRNA expression of SREBP-1c, fatty acid synthase (FAS), glycerol-3-phosphate acyltransferase (GPAT) and microsomal triglyceride transfer protein (MTP) was measured by qPCR, and SREBP-1 protein quantitated by immunohistochemistry. There was no significant difference in the hepatic expression of SREBP-1c mRNA between subjects with HCV and NDL. In patients with HCV, a significant negative relationship was seen between hepatic SREBP-1c mRNA expression and grade of steatosis ( r s = −0.28, p = 0.002), stage of fibrosis ( r s = −0.375, p < 0.001) and severity of inflammation ( r s = −0.313, p < 0.001). These relationships were observed for patients infected with either viral genotype 1 or 3. Following multivariate logistic regression analysis, hepatic SREBP-1c expression remained independently associated with fibrosis ( p = 0.008) and hepatic inflammation ( p = 0.005). HCV-infected patients with HOMA > 2 had significantly higher expression of FAS mRNA than HCV-infected subjects with HOMA ⩽ 2 ( p = 0.006) and NDL ( p = 0.016). SREBP-1c may not play a prominent role in the pathogenesis of HCV-related steatosis.