Abstract
There is growing evidence that mitochondrial dysfunction, and more specifically fatty acid β-oxidation impairment, is involved in the pathophysiology of non-alcoholic steatohepatitis (NASH). The goal of the present study was to achieve more understanding on the modification/s of carnitinepalmitoyltransferase-I (CPT-I), the rate-limiting enzyme of the mitochondrial fatty acid β-oxidation, during steatohepatitis. A high fat/methionine-choline deficient (MCD) diet, administered for 4 weeks, was used to induce NASH in rats. We demonstrated that CPT-Iactivity decreased, to the same extent, both in isolated liver mitochondria and in digitonin-permeabilized hepatocytes from MCD-diet fed rats. At the same time, the rate of total fatty acid oxidation to CO2 and ketone bodies, measured in isolated hepatocytes, was significantly lowered in treated animals when compared to controls. Finally, an increase in CPT-I mRNA abundance and protein content, together with a high level of CPT-I protein oxidation was observed in treated rats. A posttranslational modification of rat CPT-I during steatohepatitis has been here discussed.
Highlights
The term non-alcoholic steatohepatitis (NASH) describes histopathological findings typical of alcoholic liver disease in a group of patients without significant alcohol consumption [1]
NASH is observed in a subset of patients with non-alcoholic fatty liver disease (NAFLD), a pathology comprising a wide spectrum of liver damage, ranging from simple macrovescicular steatosis to steatohepatitis, advanced fibrosis, and cirrhosis [1]
The aim of the present study was to investigate whether mitochondrial CPT-I activity and fatty acid oxidation efficiencyis affected during methionine-choline deficient (MCD)-induced steatohepatitis
Summary
The term non-alcoholic steatohepatitis (NASH) describes histopathological findings typical of alcoholic liver disease in a group of patients without significant alcohol consumption [1]. NASH is observed in a subset of patients with non-alcoholic fatty liver disease (NAFLD), a pathology comprising a wide spectrum of liver damage, ranging from simple macrovescicular steatosis to steatohepatitis, advanced fibrosis, and cirrhosis [1]. Rodents fed a MCD diet develop a steatohepatitis producing hepatic lesions and changes in liver redox balance, mimicking the impairment observed in patients with NASH [9,10]. Lipid peroxidation products can react with functional groups of amino acids in proteins and enzymes to form adducts that may alter protein function [13]. This has been well demonstrated for the uncoupling protein 2 (UCP-2) in the same experimental model used in this study [7]
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