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Abstract
Cholesterol crystals form within hepatocyte lipid droplets in human and experimental nonalcoholic steatohepatitis (NASH) and are the focus of crown-like structures (CLSs) of activated Kupffer cells (KCs). Obese, diabetic Alms1 mutant (foz/foz) mice were a fed high-fat (23%) diet containing 0.2% cholesterol for 16 weeks and then assigned to four intervention groups for 8 weeks: a) vehicle control, b) ezetimibe (5 mg/kg/day), c) atorvastatin (20 mg/kg/day), or d) ezetimibe and atorvastatin. Livers of vehicle-treated mice developed fibrosing NASH with abundant cholesterol crystallization within lipid droplets calculated to extend over 3.3% (SD, 2.2%) of liver surface area. Hepatocyte lipid droplets with prominent cholesterol crystallization were surrounded by TNFα-positive (activated) KCs forming CLSs (≥ 3 per high-power field). KCs that formed CLSs stained positive for NLRP3, implicating activation of the NLRP3 inflammasome in response to cholesterol crystals. In contrast, foz/foz mice treated with ezetimibe and atorvastatin showed near-complete resolution of cholesterol crystals [0.01% (SD, 0.02%) of surface area] and CLSs (0 per high-power field), with amelioration of fibrotic NASH. Ezetimibe or atorvastatin alone had intermediate effects on cholesterol crystallization, CLSs, and NASH. These findings are consistent with a causative link between exposure of hepatocytes and KCs to cholesterol crystals and with the development of NASH possibly mediated by NLRP3 activation.
Highlights
We recently reported that cholesterol crystals were present within the lipid droplets of steatotic hepatocytes in patients with nonalcoholic steatohepatitis (NASH) and in a mouse model of NASH induced by a high-fat, high-cholesterol diet but not in patients or mice with simple steatosis [18]
We recently reported that cholesterol crystals were present in hepatocyte lipid droplets in the setting of experimental and human NASH but not in simple steatosis [18]
We demonstrate that hepatic cholesterol crystals and crown-like structure (CLS) are present in a different mouse model of Nonalcoholic fatty liver disease (NAFLD)/NASH, the foz/foz mouse on an atherogenic diet
Summary
10–30% of patients with NAFLD have or develop nonalcoholic steatohepatitis (NASH), characterized by hepatic lobular inflammation and fibrosis in addition to steatosis. The factor(s) responsible for the development of progressive NASH, as opposed to simple steatosis, remain unclear. It is generally accepted that triglycerides, which constitute the majority of hepatic lipids in NASH and simple steatosis, are a “safe” storage lipid with little or no lipotoxic potential. Lipidomic analyses of human livers with NAFLD reported that levels of free (unesterified) cholesterol (FC) were increased in NASH but not in simple steatosis, whereas levels of Abbreviations: Ath, atherogenic; CLS, crown-like structure; FC, free cholesterol; IL, interleukin; KC, Kupffer cell; NAFLD, nonalcoholic fatty liver disease; NASH, nonalcoholic steatohepatitis. Human epidemiological studies and nonrandomized clinical trials of cholesterol-lowering drugs appear to support a role of cholesterol in the development of NASH [15,16,17]
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