Docosahexaenoic acid blocks progression of western diet-induced nonalcoholic steatohepatitis in obese Ldlr-/- mice.

Kelli A Lytle,Donald B Jump,Carmen P Wong,Anna Alisi

doi:10.1371/journal.pone.0173376

Abstract

BackgroundNonalcoholic fatty liver disease (NAFLD) is a major public health concern in western societies. Nonalcoholic steatohepatitis (NASH), the progressive form of NAFLD, is characterized by hepatic steatosis, inflammation, oxidative stress and fibrosis. NASH is a risk factor for cirrhosis and hepatocellular carcinoma. NASH is predicted to be the leading cause of liver transplants by 2020. Despite this growing public health concern, there remain no Food and Drug Administration (FDA) approved NASH treatments. Using Ldlr -/- mice as a preclinical model of western diet (WD)-induced NASH, we previously established that dietary supplementation with docosahexaenoic acid (DHA, 22:6,ω3) attenuated WD-induced NASH in a prevention study. Herein, we evaluated the capacity of DHA supplementation of the WD and a low fat diet to fully reverse NASH in mice with pre-existing disease.MethodsLdlr -/- mice fed the WD for 22 wks developed metabolic syndrome (MetS) and a severe NASH phenotype, including obesity, dyslipidemia, hyperglycemia, hepatic steatosis, inflammation, fibrosis and low hepatic polyunsaturated fatty acid (PUFA) content. These mice were randomized to 5 groups: a baseline group (WDB, sacrificed at 22 wks) and 4 treatments: 1) WD + olive oil (WDO); 2) WD + DHA (WDD); 3) returned to chow + olive oil (WDChO); or 4) returned to chow + DHA (WDChD). The four treatment groups were maintained on their respective diets for 8 wks. An additional group was maintained on standard laboratory chow (Reference Diet, RD) for the 30-wk duration of the study.ResultsWhen compared to the WDB group, the WDO group displayed increased hepatic expression of genes linked to inflammation (Opn, Il1rn, Gdf15), hepatic fibrosis (collagen staining, Col1A1, Thbs2, Lox) reflecting disease progression. Mice in the WDD group, in contrast, had increased hepatic C20-22 ω3 PUFA and no evidence of NASH progression. MetS and NASH markers in the WDChO or WDChD groups were significantly attenuated and marginally different from the RD group, reflecting disease remission.ConclusionWhile these studies establish that DHA supplementation of the WD blocks WD-induced NASH progression, DHA alone does not promote full remission of diet-induced MetS or NASH.

Highlights

The Centers for Disease Control and Prevention estimate that nearly 80 million adults [1] and 13 million children [2] in the US are obese
When compared to the WDB group, the WDO group displayed increased hepatic expression of genes linked to inflammation (Opn, Il1rn, Gdf15), hepatic fibrosis reflecting disease progression
At 22 wks on the western diet (WD), obese mice were randomized to 5 groups: Group 1 mice were euthanized and served as the WD-baseline group [WDB]; Group 2 mice were fed ad libitum the WD supplemented with olive oil for 8 wks [WDO]; Group 3 mice were fed the WD supplemented with DHA for 8 wks [WD containing DHA (WDD)]; Group 4 mice were fed the Purina Pico Lab Diet 5053 chow diet supplemented with olive oil for 8 wks (WDChO); Group 5 mice were fed the Purina Pico Lab Diet 5053-chow diet supplemented with DHA for 8 wks (WDChD)

Summary

Introduction

The Centers for Disease Control and Prevention estimate that nearly 80 million adults [1] and 13 million children [2] in the US are obese. Ten to 30% of NAFLD patients develop nonalcoholic steatohepatitis (NASH) [10, 11], the progressive form of the disease. NASH has high prevalence (!60%) in the T2DM population [12]; and is recognized as a risk factor for cardiovascular disease [13,14,15]. By the year 2020, cirrhosis resulting from NASH is projected to be the leading cause of liver transplantation in the United States [17]. Nonalcoholic fatty liver disease (NAFLD) is a major public health concern in western societies. Nonalcoholic steatohepatitis (NASH), the progressive form of NAFLD, is characterized by hepatic steatosis, inflammation, oxidative stress and fibrosis. NASH is predicted to be the leading cause of liver transplants by 2020 Despite this growing public health concern, there remain no Food and Drug Administration (FDA) approved NASH treatments. We evaluated the capacity of DHA supplementation of the WD and a low fat diet to fully reverse NASH in mice with pre-existing disease

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