A moderate increase in carnitine palmitoyltransferase 1a activity is sufficient to substantially reduce hepatic triglyceride levels
A moderate increase in carnitine palmitoyltransferase 1a activity is sufficient to substantially reduce hepatic triglyceride levels
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DOI：
10.1152/ajpendo.00497.2007
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发表时间：
2008-05-01
影响因子：
5.1
通讯作者：
O'Doherty, Robert M.
中科院分区：
文献类型：
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作者：
Stefanovic-Racic, Maja;Perdomo, German;O'Doherty, Robert M.
非酒精性脂肪肝（NAFLD）、高甘油三酯血症和游离脂肪酸升高存在于大多数代谢综合征和2型糖尿病患者中，并与肝脏胰岛素抵抗密切相关。在目前的研究中，我们检验了肝脏中脂肪酸氧化速率增加将防止脂肪酸升高的潜在有害影响的假设，包括肝脏甘油三酯（TG）积累和TG分泌升高。将原代大鼠肝细胞转导编码肉毒碱棕榈酰转移酶1a（Adv-CPT-1a）的腺病毒或编码β-半乳糖苷酶（Adv-beta-gal）或肉毒碱棕榈酰转移酶2（Adv-CPT-2）的对照腺病毒。CPT-1a的过表达使β-氧化和生酮的速率增加了70%，而外源性脂肪酸的酯化和从头脂肪生成没有变化。重要的是，CPT-1a过表达伴随着肝细胞TG积累减少35%和TG分泌减少60%。载脂蛋白B（apo B）的分泌没有变化，表明合成了更小、致动脉粥样硬化性更低的VLDL颗粒。为了评价体内增加肝脏CPT-1a活性的作用，我们向瘦或肥胖雄性大鼠注射Adv-CPT-1a、Adv-beta-gal或Adv-CPT-2。与Adv-CPT-2或Adv-beta-gal给药大鼠相比，CPT-1a过表达瘦大鼠的肝脏CPT-1a活性增加了约46%，脂肪酸氧化速率增加了约44%，肥胖大鼠的脂肪酸氧化速率增加了约36%。与体外观察结果相似，通过这种体内干预，肝脏TG含量降低了37%（瘦）和69%（肥胖）。我们得出结论，CPT-1a活性的增加所实现的脂肪酸氧化的适度刺激足以在体外和体内显著降低肝脏TG蓄积。因此，增加CPT-1a活性的干预措施可能对NAFLD的治疗有潜在的益处。
Nonalcoholic fatty liver disease (NAFLD), hypertriglyceridemia, and elevated free fatty acids are present in the majority of patients with metabolic syndrome and type 2 diabetes mellitus and are strongly associated with hepatic insulin resistance. In the current study, we tested the hypothesis that an increased rate of fatty acid oxidation in liver would prevent the potentially harmful effects of fatty acid elevation, including hepatic triglyceride (TG) accumulation and elevated TG secretion. Primary rat hepatocytes were transduced adenovirus encoding carnitine palmitoyltransferase 1a (Adv-CPT-1a) or control adenoviruses encoding either beta-galactosidase (Adv-beta-gal) or carnitine palmitoyltransferase 2 (Adv-CPT-2). Overexpression of CPT-1a increased the rate of beta-oxidation and ketogenesis by similar to 70%, whereas esterification of exogenous fatty acids and de novo lipogenesis were unchanged. Importantly, CPT-1a overexpression was accompanied by a 35% reduction in TG accumulation and a 60% decrease in TG secretion by hepatocytes. There were no changes in secretion of apolipoprotein B (apoB), suggesting the synthesis of smaller, less atherogenic VLDL particles. To evaluate the effect of increasing hepatic CPT-1a activity in vivo, we injected lean or obese male rats with Adv-CPT-1a, Adv-beta-gal, or Adv-CPT-2. Hepatic CPT-1a activity was increased by similar to 46%, and the rate of fatty acid oxidation was increased by similar to 44% in lean and similar to 36% in obese CPT-1a-overexpressing animals compared with Adv-CPT-2- or Adv-beta- gal-treated rats. Similar to observations in vitro, liver TG content was reduced by similar to 37% (lean) and similar to 69% (obese) by this in vivo intervention. We conclude that a moderate stimulation of fatty acid oxidation achieved by an increase in CPT-1a activity is sufficient to substantially reduce hepatic TG accumulation both in vitro and in vivo. Therefore, interventions that increase CPT-1a activity could have potential benefits in the treatment of NAFLD.