Is Western Diet-Induced Nonalcoholic Steatohepatitis <i>in Ldlr^-/-</i> Mice Reversible?

Abstract

<div><p>Background</p><p>Nonalcoholic fatty liver disease (<b>NAFLD</b>) is a major public health burden in western societies. The progressive form of NAFLD, nonalcoholic steatohepatitis (<b>NASH</b>), 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.</p><p>Methods</p><p>We evaluated the efficacy of two diets, a non-purified chow (<b>NP</b>) and purified (low-fat low-cholesterol, <b>LFLC</b>) diet to reverse western diet (<b>WD</b>)-induced NASH and fibrosis in <i>Ldlr</i>^<i>-/-</i> mice.</p><p>Results</p><p>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 (<i>Mcp1</i>), oxidative stress (<i>Nox2</i>), fibrosis (<i>Col1A</i>, <i>LoxL2</i>, <i>Timp1</i>) and collagen crosslinking (hydroxyproline). Time course analyses established that plasma triglycerides and hepatic <i>Col1A1</i> 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 (<i>Col1A</i>, <i>Timp1</i>, <i>LoxL2</i>). Inflammation and fibrosis markers were inversely associated (r² ≥ 0.32) with diet-induced changes in hepatic ω3 and ω6 polyunsaturated fatty acids (<b>PUFA</b>) content.</p><p>Conclusion</p><p>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 <i>Ldlr</i>^<i>-/-</i> mice.</p></div