Polyunsaturated fat in the methionine-choline-deficient diet influences hepatic inflammation but not hepatocellular injury

Jim S. Yan,Sanjay Kakar,Gene S. Lee,Raymond K. Ng,Jacquelyn J. Maher

doi:10.1194/jlr.m700181-jlr200

Jim S. Yan, Sanjay Kakar + Show 3 more

Open Access

https://doi.org/10.1194/jlr.m700181-jlr200

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Abstract

Methionine-choline-deficient (MCD) diets that cause steatohepatitis in rodents are typically enriched in polyunsaturated fat. To determine whether the fat composition of the MCD formula influences the development of liver disease, we manufactured custom MCD formulas with fats ranging in PUFA content from 2% to 59% and tested them for their ability to induce steatohepatitis. All modified-fat MCD formulas caused identical degrees of hepatic steatosis and resulted in a similar distribution of fat within individual hepatic lipid compartments. The fatty acid composition of hepatic lipids, however, reflected the fat composition of the diet. Mice fed a PUFA-rich MCD formula showed extensive hepatic lipid peroxidation, induction of proinflammatory genes, and histologic inflammation. When PUFAs were substituted with more saturated fats, lipid peroxidation, proinflammatory gene induction, and hepatic inflammation all declined significantly. Despite the close relationship between PUFAs and hepatic inflammation in mice fed MCD formulas, dietary fat had no impact on MCD-mediated damage to hepatocytes. Indeed, histologic apoptosis and serum alanine aminotransferase levels were comparable in all MCD-fed mice regardless of dietary fat content. Together, these results indicate that dietary PUFAs promote hepatic inflammation but not hepatotoxicity in the MCD model of liver disease. These findings emphasize that individual dietary nutrients can make specific contributions to steatohepatitis.

Highlights

Methionine-choline-deficient (MCD) diets that cause steatohepatitis in rodents are typically enriched in polyunsaturated fat
The current study demonstrates that polyunsaturated fatty acids, which are the main constituents of corn oil, are directly responsible for the hepatic lipid peroxidation and much of the hepatic inflammation that occur in mice fed commercial MCD diets
Removal of unsaturated fat from the MCD formula results in significant suppression of MCD-mediated hepatic inflammation; it does not, have any impact on MCD-mediated injury to hepatocytes. These findings indicate that hepatocellular injury and hepatic inflammation are distinct pathophysiologic events in MCD-fed mice, which may provide an important clue to the pathogenesis of liver disease in this animal model of steatohepatitis

Summary

Introduction

Methionine-choline-deficient (MCD) diets that cause steatohepatitis in rodents are typically enriched in polyunsaturated fat. Changing the fat composition of the MCD diet from corn oil to either beef tallow or coconut oil did not affect the degree of hepatic steatosis in MCD-fed mice (Table 2).

Results

Conclusion