No abstract

Non-alcoholic fatty liver disease (NAFLD) is intricately linked to metabolic disease (inluding obesity, glucose intolerance, and insulin resistance) and encompasses a spectrum of disorders including steatosis, non-alcoholic steatohepatitis (NASH) and fibrosis. Rodents consuming a high fat (HF, around 40 kcal% fat including fats containing higher levels of saturated and trans-fats), high fructose (HFr) and high cholesterol (HC) diets display many clinically relevant characteristics of NASH, along with other metabolic disorders. C57BL/6 mice are the most commonly used animal model as they can develop significant metabolic disorders including severe NASH with fibrosis after months of feeding, but other models also are susceptible. The significant number of diets that contain these different factors (i.e. HF, HFr, and HC), either alone or in combination, makes the choice of diet difficult. This methodology review describes the efficacy of these nutrient manipulations on the NAFLD phenotype in mice, rats, guinea pigs, hamsters, and non-human primates.

Hepatic steatosis is an obesity‐triggered fatty liver disease in which the liver becomes vulnerable to oxidative insults resulting in nonalcoholic steatohepatitis (NASH). We hypothesized that α‐ or γ‐tocopherol (α‐ or γ‐T) supplementation during hepatic steatosis would decrease the progression towards LPS‐induced NASH. Five‐wk old obese (ob/ob) and lean littermate mice were fed a control, α‐T, or γ‐T supplemented diet (1000 mg/kg) for 5 wk (18 mice/genotype/diet) and then injected with LPS prior to sacrifice at 0, 1.5 or 6 h. Obese compared to lean mice had ∼40% greater (p<0.05) body weight and >3‐times hepatic lipid which were unaffected by Ts or LPS. Obese compared to lean mice had greater hepatic Ts. T supplementation further increased hepatic α‐ and γ‐T by 9.7 and 10.1‐times respectively, compared to respective obese controls. LPS reduced hepatic Ts at 6 h compared to 0 and 1.5 h in obese mice. Obese mice had higher serum alanine aminotransferase (ALT) and α‐ and γ‐T supplementation in obese mice similarly reduced LPS‐induced increases in ALT at 1.5 and 6 h. α‐ and γ‐T supplementation decreased hepatic ascorbic acid (AA) in obese mice and LPS increased AA at 6 h. These data suggest that α‐ or γ‐T protected against LPS‐induced hepatic injury in obese mice likely through a common mechanism not involving AA. Additional study is underway to define the protective mechanism of T supplementation against NASH.

Carbohydrate restriction (CR) improves parameters of metabolic syndrome and inflammation, but effects on hepatic lipids and antioxidants are less clear. To test the hypothesis that CR favorably affects hepatic oxidative stress and lipids, we assessed hepatic lipids and antioxidants in retired breeder guinea pigs fed a low (L‐) or high (H‐) carbohydrate (CARB) diet with low (0.04%) or high (0.25%) cholesterol (CHOL) for 12 wk (n = 10/dietary treatment). Liver weight was increased by H‐CHOL (p<0.001) and L‐CARB (p<0.05). Guinea pigs fed H‐CHOL had increased (p<0.001) hepatic triglyceride and cholesterol while CARB did not affect hepatic lipids. LCARB increased (p<0.001) hepatic and plasma α‐tocopherol (α‐T) by 1.8 and 4‐times, respectively, whereas H‐CHOL decreased hepatic (p=0.06) and plasma (p<0.05) α‐T by 24% and 54%. Hepatic glutathione ratio (GSH/GSSG) decreased 30% with L‐CARB (p<0.01) and 29% with H‐CHOL (p<0.001), and was due to higher GSSG (p<0.01) and unchanged GSH. GSSG was inversely related (r = ‐0.370; p<0.05) to hepatic α‐T. Hepatic ascorbic acid and uric acid were unaffected by CARB and CHOL. These data suggest that L‐CARB and H‐CHOL result in an oxidative shift of hepatic thiol redox status while L‐CARB improved α‐T status in plasma and liver in aged guinea pigs.