Cheng Xiaoyun, Yamauchi Jun, Lee Sojin, Zhang Ting, Gong Zhenwei, Muzumdar Radhika, Qu Shen, Dong H Henry
From the Department of Endocrinology and Metabolism, Shanghai 10th People's Hospital, Tongji University School of Medicine, Shanghai 200072, China and.
the Division of Endocrinology and Diabetes, Department of Pediatrics, Children's Hospital of Pittsburgh of UPMC, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15224.
J Biol Chem. 2017 Mar 3;292(9):3692-3705. doi: 10.1074/jbc.M116.765917. Epub 2017 Jan 23.
Nonalcoholic fatty liver disease (NAFLD), characterized by excessive fat accumulation in liver, is prevalent in obesity. Genetic factors that link obesity to NAFLD remain obscure. Apolipoprotein C3 (APOC3) is a lipid-binding protein with a pivotal role in triglyceride metabolism. Humans with APOC3 gain-of-function mutations and mice with APOC3 overproduction are associated with hypertriglyceridemia. Nonetheless, it remains controversial whether APOC3 is culpable for diet-induced NAFLD. To address this fundamental issue, we fed APOC3-transgenic and wild-type littermates a high fructose diet or high fat diet, followed by determination of the effect of APOC3 on hepatic lipid metabolism and inflammation and the progression of NAFLD. To gain mechanistic insight into NAFLD, we determined the impact of APOC3 on hepatic triglyceride synthesis and secretion fatty acid oxidation. APOC3-transgenic mice were hypertriglyceridemic, culminating in marked elevation of triglycerides, cholesterols, and non-esterified fatty acids in plasma. Despite the prevailing hypertriglyceridemia, APOC3-transgenic mice, relative to wild-type littermates, had similar weight gain and hepatic lipid content without alterations in hepatic expression of key genes involved in triglyceride synthesis and secretion and fatty acid oxidation. APOC3-transgenic and wild-type mice had similar Kupffer cell content without alterations in hepatic expression of pro- and anti-inflammatory cytokines. APOC3 neither exacerbated diet-induced adiposity nor aggravated the degree of steatosis in high fructose or high fat-fed APOC3-transgenic mice. These effects ensued independently of weight gain even after 10-month high fat feeding. We concluded that APOC3, whose dysregulation is liable for hypertriglyceridemia, is not a predisposing factor for linking overnutrition to NAFLD in obesity.
非酒精性脂肪性肝病（NAFLD）以肝脏中脂肪过度蓄积为特征，在肥胖人群中普遍存在。将肥胖与NAFLD联系起来的遗传因素仍不清楚。载脂蛋白C3（APOC3）是一种脂质结合蛋白，在甘油三酯代谢中起关键作用。携带APOC3功能获得性突变的人和APOC3过度产生的小鼠与高甘油三酯血症有关。然而，APOC3是否是饮食诱导的NAFLD的罪魁祸首仍存在争议。为了解决这个基本问题，我们给APOC3转基因小鼠和野生型同窝小鼠喂食高果糖饮食或高脂肪饮食，然后测定APOC3对肝脏脂质代谢、炎症以及NAFLD进展的影响。为了深入了解NAFLD的机制，我们测定了APOC3对肝脏甘油三酯合成、分泌及脂肪酸氧化的影响。APOC3转基因小鼠出现高甘油三酯血症，最终导致血浆中甘油三酯、胆固醇和非酯化脂肪酸显著升高。尽管存在普遍的高甘油三酯血症，但与野生型同窝小鼠相比，APOC3转基因小鼠的体重增加和肝脏脂质含量相似，参与甘油三酯合成、分泌及脂肪酸氧化的关键基因的肝脏表达没有改变。APOC3转基因小鼠和野生型小鼠的库普弗细胞含量相似，促炎和抗炎细胞因子的肝脏表达没有改变。在高果糖或高脂肪喂养的APOC3转基因小鼠中，APOC3既没有加剧饮食诱导的肥胖，也没有加重脂肪变性程度。即使在高脂肪喂养10个月后，这些影响也与体重增加无关。我们得出结论，APOC3的失调易导致高甘油三酯血症，但它不是将肥胖中的营养过剩与NAFLD联系起来的 predisposing factor（此处predisposing factor未翻译，可能是专业术语，需要根据上下文进一步明确其准确含义）。
