Abstract
BackgroundNonalcoholic 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.MethodsWe 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.ResultsMice 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.ConclusionThese 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.
Highlights
Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic fatty liver disease in the United States affecting 10–35% of adults and an increasing number of children [1,2,3]
We evaluated the efficacy of two diets, a non-purified chow (NP) and purified diet to reverse western diet (WD)-induced nonalcoholic steatohepatitis (NASH) and fibrosis in Ldlr-/- mice
Time course analyses established that plasma triglycerides and hepatic Collagen 1A1 (Col1A1) mRNA were rapidly reduced following the switch from the WD to the low-fat low-cholesterol (LFLC) diet
Summary
Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic fatty liver disease in the United States affecting 10–35% of adults and an increasing number of children [1,2,3]. NAFLD is primarily characterized by excess deposition of neutral lipid (hepatosteatosis) in the liver in which >5% of the liver is stored neutral lipid (triglycerides & cholesterol esters). Hepatosteatosis can progress to nonalcoholic steatohepatitis (NASH). NASH is characterized by hepatic inflammation, hepatocyte damage/death and oxidative stress. Excessive damage to the liver promotes fibrosis, i.e., deposition of extracellular matrix (ECM), consisting of collagens, elastin and other proteins. NASH-associated fibrosis is a risk factor for cirrhosis and primary hepatocellular carcinoma. 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.
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