A high‐fat diet leads to the progression of non‐alcoholic fatty liver disease in obese rats

Abstract

To read the full text of this article, go to http://www.fasebj.org/cgi/ SPECIFIC AIMSToxic by-products of lipid peroxidation and oxidative stress associated with increased fat deposition in the liver, cytokine-mediated injury, and hyperglycemia are among proposed mechanisms that trigger fatty liver disease. It is uncertain why only a subgroup of patients with nonalcoholic steatohepatitis (NASH) may progress to liver fibrosis. Fatty livers of obese fa/fa rats are vulnerable to injury when challenged by endotoxin, ischemia-reperfusion, or acute ethanol treatment. Since the prevalence of obesity is expected to rise in the near future due to high saturated fat consumption, the objective of this study was to evaluate whether a high fat diet (HFD) can act as a "second hit" and cause progression to liver injury in obese fa/fa rats compared with lean Fa/? rats. PRINCIPAL FINDINGS A high saturated fat diet (HFD) contributes to the progression of NASH to fibrosisFifteen-wk-old obese fa/fa Zucker rats and their lean littermates, Fa/? rats, were fed a control or a high fat diet (12% vs. 60% total calories, respectively) for 8 wk. Hyperglycemia occurred to the greatest extent in fa/fa rats fed the HFD. Liver injury appeared in fa/fa rats fed the HFD. Hematoxylin and eosin staining showed steatohepatitis, ballooning degeneration, significant macrosteatosis extending beyond the periportal area into the lobule and the central zone, and foci of lobular inflammation only in the fa/fa rats fed the HFD (Fig. 1A-D). Nonesterified fatty acid levels were elevated 2-fold in fa/fa rats fed the HFD compared with control diet (Fig. 1E). ALT values were 5-fold higher than in Fa/? rats (Fig. 1F ). Stellate cell-derived TGF␤, which actively participates in liver fibrosis and collagen deposition, and plasma TNF␣ increased in fa/fa rats fed HFD compared with fa/fa rats fed control diet or to Fa/? rats fed HFD.Sirius red/Fast green staining for collagenous proteins showed mild periportal fibrosis only in fa/fa rats fed HFD. Western blot analysis for collagen type I, a marker of liver fibrosis, revealed increased collagen I expression in the liver of fa/fa rats fed HFD; no change was observed with Fa/? rats. ␣-Smooth muscle actin, representative of stellate cell activation, was elevated in fa/fa rats fed HFD. Expression of matrix metalloproteinases (MMPs) that participate in collagen degradation as well as their inhibitors (tissue inhibitors of metalloproteinases, TIMPs) was analyzed. A decrease in pro-MMP13 and active MMP13 was found in fa/fa rats regardless of diet. TIMP1 (which inhibits MMP13, preventing collagen I degradation) was similar in both genotypes fed control diet but elevated in rats fed HFD, especially in fa/fa rats. Along with elevated TGF␤ production, this may contribute to collagen accumulation in fa/fa rats fed HFD. MMP2 and MMP9 were detected only as latent forms by Western blot analysis; pro-MMP9 was increased 2-fold in fa/fa rats regardless of diet. Oxidative stress in obese fa/fa rats fed HFDFormation of malondialdehyde, a...

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