Liver international : official journal of the International Association for the Study of the Liver
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Comparative Study
Strain dependence of diet-induced NASH and liver fibrosis in obese mice is linked to diabetes and inflammatory phenotype.
Obese Alms1 mutant (foz/foz) NOD.B10 mice develop diabetes and fibrotic NASH when fed high-fat(HF) diet. To establish whether diabetes or obesity is more closely associated with NASH fibrosis, we compared diabetic foz/foz C57BL6/J with non-diabetic foz/foz BALB/c mice. We also determined hepatic cytokines, growth factors and related profibrotic pathways. ⋯ In mice with equivalent genetic/dietary obesity, NASH development is linked to strain differences in hyperinsulinaemia and hyperglycaemia inversely related to lipid partitioning between adipose and liver. Diabetes-mediated CTGF-regulation of MMPs as well as cytokines/growth factors (Th-2 cytokine predominant, PDGFα, not TGF-β) mobilized in the resultant hepatic necroinflammatory change may contribute to strain differences in NASH fibrosis.
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Nonalcoholic fatty liver disease (NAFLD) is an insulin resistance-related hepatic disorder which can transform to cirrhosis. Insulin resistance deregulates hepatic lipid metabolism, leading to accumulation of cytotoxic lipids including ceramide and diacylglycerols. Myriocin, obtained from fungi traditionally used in Chinese medicine in an effort to attain eternal youth, is a potent pharmacological inhibitor of ceramide de novo synthesis. We examined whether inhibition of ceramide de novo synthesis with myriocin ameliorate hepatic lipid accumulation and reverse NAFLD. ⋯ Inhibition of ceramide de novo synthesis reduced hepatic lipid accumulation in rats with NAFLD, this led to amelioration of hepatic steatosis.