PPARα activation is essential for HCV core protein–induced hepatic steatosis and hepatocellular carcinoma in mice

Abstract

Transgenic mice expressing HCV core protein develop hepatic steatosis and hepatocellular carcinoma (HCC), but the mechanism underlying this process remains unclear. Because PPARα is a central regulator of triglyceride homeostasis and mediates hepatocarcinogenesis in rodents, we determined whether PPARα contributes to HCV core protein-induced diseases. We generated PPARα-homozygous, -heterozygous, and -null mice with liver-specific transgenic expression of the core protein gene (Ppara +/+ :HCVcpTg, Ppara +/-:HCVcpTg, and Ppara -/-:HCVcpTg mice. Severe steatosis was unexpectedly observed only in Ppara +/+ :HCVcpTg mice, which resulted from enhanced fatty acid uptake and decreased mitochondrial β-oxidation due to breakdown of mitochondrial outer membranes. Interestingly, HCC developed in approximately 35% of 24-month-old Ppara +/+ : HCVcpTg mice, but tumors were not observed in the other genotypes. These phenomena were found to be closely associated with sustained PPARα activation. In Ppara +/-:HCVcpTg mice, PPARα activation and the related changes did not occur despite the presence of a functional Ppara allele. However, long-term treatment of these mice with clofibrate, a PPARα activator, induced HCC with mitochondrial abnormalities and hepatic steatosis. Thus, our results indicate that persistent activation of PPARα is essential for the pathogenesis of hepatic steatosis and HCC induced by HCV infection. IntroductionHCV is one of the major causes of chronic hepatitis, whereas patients with persistent HCV infection have a high incidence of hepatocellular carcinoma (HCC) (1, 2). Occurrence of HCC associated with chronic HCV infection has increased over the past 2 decades (3-5), and chronic HCV infection is recognized as a serious debilitating disease. However, the mechanism in which chronic HCV infection mediates hepatocarcinogenesis remains unclear.HCV core protein was shown to have oncogenic potential (6). To examine how HCV core protein participates in HCV-related hepatocarcinogenesis, transgenic mouse lines were established in which HCV core protein is expressed constitutively in liver at cellular levels similar to those found in chronic HCV-infected patients (7). These mice exhibited hepatic steatosis (7) and insulin resistance (8) as early as 3 months of age; on further aging, these symptoms worsened and hepatic adenomas developed in approximately 30% of mice between 16 and 18 months of age (9). Finally, HCC was found within hepatic adenomas in a classic "nodule-in-nodule" pathology (9). Interestingly, no hepatic inflammation or fibrosis was found in these mice throughout

Western diet in ApoE-LDLR double-deficient mouse model of atherosclerosis leads to hepatic steatosis, fibrosis, and tumorigenesis

“…28 Further, in light of the increased proteins levels of FASN in AL mice on WD, increased steatosis might very well be ascribed to enhanced hepatic biosynthesis of triglycerides. This observation is consistent with findings from other studies, which were able to demonstrate the induction of triglyceride synthesis in the liver of diet-induced obesity and NAFLD.…”

Peroxisome proliferator-activated receptor α mediates enhancement of gene expression of cerebroside sulfotransferase in several murine organs

“…PPARα maintains the constitutive expression of genes for several enzymes that are involved in the mitochondrial fatty acid β-oxidation system, such as long-chain acyl-CoA synthetase, and PPARα activation induces gene expression of these enzymes and stimulates β-oxidation [11, [38][39][40][41][42][43]. Because the synthesis of sphingolipids is initiated by the transfer of L-serine onto activated long-chain fatty acids, such as palmitoyl-CoA, which arises from the reaction with long-chain acyl-CoA synthetase [44], PPARα presumably participates in the regulation of overall sphingolipid metabolism.…”

Risk for Renal Cell Carcinoma in Chronic Hepatitis C Infection

“…In transgenic mice, constitutive expression of HCV core protein can induce hepatocellular carcinoma (23). There is evidence that activation of peroxisome proliferator-activated receptor α, which regulates transcription of genes encoding fatty acid-metabolizing enzymes, is essential for the induction of hepatocellular carcinoma by HCV core protein (24). The precise mechanisms by which HCV leads to hepatocellular carcinoma, however, are not clear at this time nor is it known whether similar mechanisms could be implicated in RCC.…”