Diet rich in Docosahexaenoic Acid/Eicosapentaenoic Acid robustly ameliorates hepatic steatosis and insulin resistance in seipin deficient lipodystrophy mice

Background: N-3 polyunsaturated fatty acids (n-3 PUFAs), in particular eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), have been shown to effectively improve hepatic steatosis and insulin resistance caused by obesity. Lipodystrophy could also develop insulin resistance and hepatic steatosis. However, the effect of supplemental DHA/EPA to hepatic steatosis caused by lipodystrophy is unknown. In this study, we investigated whether a diet rich in n-3 PUFAs could ameliorate severe steatosis in lipoatrophic seipin gene knockout (SKO) mice. Methods: Eight-week-old C57BL/6 J WT and SKO mice were fed with normal chow diet (NC), or 2 % DHA/EPA (3:1) diet for 12 weeks. Total cholesterol (TC) and triglycerides (TG) in plasma and liver, plasma high density lipoprotein-cholesterol (HDL-C), glucose (Glu), insulin, leptin and adiponectin levels were measured. Gene regulations and protein levels were investigated using quantitative PCR and western blot in liver. Results: We found that the DHA/EPA diet protected against hepatic steatosis effectively in SKO mice morphologically. Hepatic TG content was decreased about 40 % (p < 0.05) in SKO mice fed with the DHA/EPA diet compared to chow fed SKO controls. Glucose and insulin tolerance were also improved significantly in SKO mice with DHA/EPA diet. In analyzing hepatic gene expression pattern it was found that TG synthesis related genes, such as carbohydrate response element binding protein (ChREBP), stearoyl-CoA desaturase 1 (SCD1) and fatty acid synthase (Fas) were upregulated in SKO mice compared to WT mice but were significantly decreased in SKO mice on DHA/EPA diet. Fatty acid beta-oxidation related genes, on the other hand, such as peroxisome proliferator-activated receptor a (PPAR alpha), carnitine palmitoyltransferase (CPT) and acyl-CoA oxidase 1 (ACOX1) were elevated in both WT and SKO groups on DHA/EPA diets. The protein levels of PPAR alpha, SCD1, CPT1 alpha, Insulin receptor substrate 1 (IRS1) and ratio of p-AKT to AKT showed the same tendency as the result of genes expressions. Conclusions: The results suggest that n-3 PUFAs rich diet ameliorates lipodystrophy-induced hepatic steatosis through reducing TG synthesis, improving insulin resistance and enhancing beta-oxidation in SKO mice.