TitleIs Western Diet-Induced Nonalcoholic Steatohepatitis in Ldlr-/- Mice Reversible?
Publication TypeJournal Article
Year of Publication2016
AuthorsLytle KA, Jump DB
JournalPLoS One
Date Published2016
KeywordsAnimals, Body Weight, Carcinoma, Hepatocellular, Diet, Fat-Restricted, Diet, Western, Dietary Fats, Disease Progression, Fatty Acids, Fatty Acids, Unsaturated, Fibrosis, Gene Expression Regulation, Inflammation, Lipids, Liver, Liver Cirrhosis, Liver Neoplasms, Male, Mice, Mice, Knockout, Non-alcoholic Fatty Liver Disease, Oxidative Stress, Receptors, LDL, Risk Factors, Time Factors, Triglycerides

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is a major public health burden in western societies. The progressive form of NAFLD, nonalcoholic steatohepatitis (NASH), is characterized by hepatosteatosis, inflammation, oxidative stress, and hepatic damage that can progress to fibrosis and cirrhosis; risk factors for hepatocellular carcinoma. Given the scope of NASH, validating treatment protocols (i.e., low fat diets and weight loss) is imperative.

METHODS: We evaluated the efficacy of two diets, a non-purified chow (NP) and purified (low-fat low-cholesterol, LFLC) diet to reverse western diet (WD)-induced NASH and fibrosis in Ldlr-/- mice.

RESULTS: Mice fed WD for 22-24 weeks developed robust hepatosteatosis with mild fibrosis, while mice maintained on the WD an additional 7-8 weeks developed NASH with moderate fibrosis. Returning WD-fed mice to the NP or LFLC diets significantly reduced body weight and plasma markers of metabolic syndrome (dyslipidemia, hyperglycemia) and hepatic gene expression markers of inflammation (Mcp1), oxidative stress (Nox2), fibrosis (Col1A, LoxL2, Timp1) and collagen crosslinking (hydroxyproline). Time course analyses established that plasma triglycerides and hepatic Col1A1 mRNA were rapidly reduced following the switch from the WD to the LFLC diet. However, hepatic triglyceride content and fibrosis did not return to normal levels 8 weeks after the change to the LFLC diet. Time course studies further revealed a strong association (r2 ≥ 0.52) between plasma markers of inflammation (TLR2 activators) and hepatic fibrosis markers (Col1A, Timp1, LoxL2). Inflammation and fibrosis markers were inversely associated (r2 ≥ 0.32) with diet-induced changes in hepatic ω3 and ω6 polyunsaturated fatty acids (PUFA) content.

CONCLUSION: These studies establish a temporal link between plasma markers of inflammation and hepatic PUFA and fibrosis. Low-fat low-cholesterol diets promote reversal of many, but not all, features associated with WD-induced NASH and fibrosis in Ldlr-/- mice.

Alternate JournalPLoS ONE
PubMed ID26761430
PubMed Central IDPMC4711955
Grant ListR01 DK094600 / DK / NIDDK NIH HHS / United States
DK094600 / DK / NIDDK NIH HHS / United States