Prevention/reversal of choline deficiency-induced steatohepatitis by a peroxisome proliferator-activated receptor α ligand in rats

Nonalcoholic steatohepatitis, often associated with obesity and diabetes, is a common liver condition in the U.S. Individuals with steatohepatitis are not eligible for liver donation and may be at increased risk from developing complications following lobectomy. If steatosis and steatohepatitis can be treated medically, these individuals can become eligible for living donor transplants and segmental resection of the liver for treatment of primary or metastatic liver diseases. Because rats fed a choline-deficient diet (CDD) develop morphological changes in the liver similar to that observed in nonalcoholic steatohepatitis, we examined the effect of ciprofibrate, a potent peroxisome proliferator activated receptor α (PPARα) ligand and inducer of fatty acid oxidation systems in the liver, on reversal of steatosis. Rats fed CDD for 2 weeks developed marked fatty change with mild hepatitis and marked increase in serum aminotransferases and liver triacylglycerols. Concurrent administration of CDD and ciprofibrate resulted in the prevention of fatty change. Rats that were fed CDD for 2 weeks followed by feeding CDD containing ciprofibrate for 1 or 2 weeks resulted in marked reduction of fatty change and normalization of serum aminotransferases. Compared with the CDD group, all groups that received ciprofibrate showed several-fold increase in mRNA and protein levels of several PPARα target genes. In addition, electron microscopic examination showed marked peroxisome proliferation in the hepatocytes. The results of these studies clearly demonstrate that the severity of CDD-induced fatty change and hepatitis in rats can be rapidly decreased by ciprofibrate and suggest the therapeutic potential of PPARα ligands in the treatment of nonalcoholic steatohepatitis in humans to rapidly reverse liver changes.