Ioannou George N, Van Rooyen Derrick M, Savard Christopher, Haigh W Geoffrey, Yeh Matthew M, Teoh Narci C, Farrell Geoffrey C
Division of Gastroenterology, Department of Medicine, Veterans Affairs Puget Sound Health Care System and University of Washington, Seattle, WA.
Liver Research Group, Australian National University Medical School at the Canberra Hospital, Garran, ACT, Australia.
J Lipid Res. 2015 Feb;56(2):277-85. doi: 10.1194/jlr.M053785. Epub 2014 Dec 17.
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.
在人类和实验性非酒精性脂肪性肝炎（NASH）中，胆固醇晶体在肝细胞脂滴内形成，并且是活化的库普弗细胞（KC）的冠状结构（CLS）的焦点。将肥胖、糖尿病的Alms1突变（foz/foz）小鼠喂食含0.2%胆固醇的高脂肪（23%）饮食16周，然后分为四个干预组，持续8周：a）载体对照，b）依泽替米贝（5mg/kg/天），c）阿托伐他汀（20mg/kg/天），或d）依泽替米贝和阿托伐他汀。载体处理小鼠的肝脏发生纤维化NASH，脂滴内有大量胆固醇结晶，计算得出其覆盖肝脏表面积的3.3%（标准差，2.2%）。具有明显胆固醇结晶的肝细胞脂滴被TNFα阳性（活化）的KC包围，形成CLS（每高倍视野≥3个）。形成CLS的KC对NLRP3染色呈阳性，提示NLRP3炎性小体因胆固醇晶体而活化。相比之下，用依泽替米贝和阿托伐他汀治疗的foz/foz小鼠胆固醇结晶[表面积的0.01%（标准差，0.02%）]和CLS（每高倍视野0个）几乎完全消退，纤维化NASH得到改善。单独使用依泽替米贝或阿托伐他汀对胆固醇结晶、CLS和NASH有中等程度的影响。这些发现与肝细胞和KC暴露于胆固醇晶体之间的因果关系以及NASH的发展可能由NLRP3激活介导一致。
