Caspase-2 promotes obesity, the metabolic syndrome and nonalcoholic fatty liver disease.
Caspase-2 promotes obesity, the metabolic syndrome and nonalcoholic fatty liver disease.
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DOI：
10.1038/cddis.2016.19
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发表时间：
2016-02-18
影响因子：
9
通讯作者：
Diehl AM
中科院分区：
文献类型：
--
作者：
Machado MV;Michelotti GA;Jewell ML;Pereira TA;Xie G;Premont RT;Diehl AM
肥胖及其导致的代谢紊乱是主要的健康威胁。为了应对能量过剩，过度负荷的脂肪细胞释放脂肪酸和促炎因子进入循环，促进器官脂肪积累（包括非酒精性脂肪肝），胰岛素抵抗和代谢综合征。最近，caspase-2与脂凋亡有关，因此我们假设caspase-2可能是代谢综合征发病机制的关键决定因素。Caspase-2缺陷型和野生型小鼠喂食西方饮食（高脂肪饮食，富含饱和脂肪酸和0.2%胆固醇，在饮用水中补充果糖和葡萄糖）16周。评价代谢和肝脏结局。体外研究评估了caspase-2在脂肪组织增殖特性和脂凋亡易感性中的作用。喂食西方饮食的Caspase-2缺陷小鼠可避免腹部脂肪沉积、糖尿病、血脂异常和肝脂肪变性。caspase-2缺陷小鼠的脂肪组织增殖性更强，线粒体解偶联蛋白上调与布朗宁一致，并且对细胞肥大和细胞死亡具有抵抗力。通过减少循环脂肪酸和更有效的肝脏脂肪代谢，保护肝脏免受脂肪性肝炎的影响，并通过减少脂毒性肝细胞的纤维化刺激，防止纤维化。Caspase-2缺乏可保护小鼠免受饮食诱导的肥胖、代谢综合征和非酒精性脂肪性肝病的影响。进一步的研究是必要的，以评估caspase-2作为这些条件的治疗靶点。
Obesity and its resulting metabolic disturbances are major health threats. In response to energy surplus, overtaxed adipocytes release fatty acids and pro-inflammatory factors into the circulation, promoting organ fat accumulation (including nonalcoholic fatty liver disease), insulin resistance and the metabolic syndrome. Recently, caspase-2 was linked to lipoapoptosis, so we hypothesized that caspase-2 might be a critical determinant of metabolic syndrome pathogenesis. Caspase-2-deficient and wild-type mice were fed a Western diet (high-fat diet, enriched with saturated fatty acids and 0.2% cholesterol, supplemented with fructose and glucose in the drinking water) for 16 weeks. Metabolic and hepatic outcomes were evaluated. In vitro studies assessed the role of caspase-2 in adipose tissue proliferative properties and susceptibility for lipoapoptosis. Caspase-2-deficient mice fed a Western diet were protected from abdominal fat deposition, diabetes mellitus, dyslipidemia and hepatic steatosis. Adipose tissue in caspase-2-deficient mice was more proliferative, upregulated mitochondrial uncoupling proteins consistent with browning, and was resistant to cell hypertrophy and cell death. The liver was protected from steatohepatitis through a decrease in circulating fatty acids and more efficient hepatic fat metabolism, and from fibrosis as a consequence of reduced fibrogenic stimuli from fewer lipotoxic hepatocytes. Caspase-2 deficiency protected mice from diet-induced obesity, metabolic syndrome and nonalcoholic fatty liver disease. Further studies are necessary to assess caspase-2 as a therapeutic target for those conditions.