Differential hepatotoxicity of dietary and DNL-derived palmitate in the methionine-choline-deficient model of steatohepatitis

BMC Gastroenterology

Jacquelyn J. Maher¹  James P. Grenert³  Kevin Siao¹  Michael K. Pickens²  Andrew A. Pierce¹ 

[1] Department of Medicine, University of California San Francisco, San Francisco, USA;Liver Center Laboratory, San Francisco General Hospital, University of California San Francisco, 1001 Potrero Avenue, Building 40, Room 4102, San Francisco, 94110, CA, USA;Department of Pathology, University of California San Francisco, San Francisco, USA

关键词: Macronutrient;    De novo lipogenesis;    Saturated fat;    Lipotoxicity;    Fatty liver;    Liver;   

Others  :  1223128
DOI  :  10.1186/s12876-015-0298-y

 received in 2015-02-03, accepted in 2015-06-05,  发布年份 2015

【 摘 要 】

Background

Saturated fatty acids are toxic to liver cells and are believed to play a central role in the pathogenesis of non-alcoholic steatohepatitis. In experimental steatohepatitis induced by feeding mice a methionine-choline-deficient (MCD) diet, the degree of liver damage is related to dietary sugar content, which drives de novo lipogenesis and promotes the hepatic accumulation of saturated fatty acids. The objective of this study was to determine whether dietary palmitate exerts the same toxicity as carbohydrate-derived palmitate in the MCD model of fatty liver disease.

Methods

We fed mice custom MCS and MCD formulas containing 4 different carbohydrate-fat combinations: starch-oleate, starch-palmitate, sucrose-oleate and sucrose-palmitate.  After 3 wk, we compared their metabolic and disease outcomes.

Results

Mice fed the custom MCD formulas developed varying degrees of hepatic steatosis and steatohepatitis, in the order starch-oleate < starch-palmitate < sucrose-oleate < sucrose-palmitate. Liver injury correlated positively with the degree of hepatic lipid accumulation. Liver injury also correlated positively with the amount of palmitate in the liver, but the relationship was weak. Importantly, mice fed MCD starch-palmitate accumulated as much hepatic palmitate as mice fed MCD sucrose-oleate, yet their degree of liver injury was much lower. By contrast, mice fed MCD sucrose-palmitate developed severe liver injury, worse than that predicted by an additive influence of the two nutrients.

Conclusion

In the MCD model of steatohepatitis, carbohydrate-derived palmitate in the liver is more hepatotoxic than dietary palmitate. Dietary palmitate becomes toxic when combined with dietary sugar in the MCD model, presumably by enhancing hepatic de novo lipogenesis.

【 授权许可】

   
2015 Pierce et al.

【 图 表 】

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