Acute hepatic steatosis in mice by blocking β-oxidation does not reduce insulin sensitivity of very-low-density lipoprotein production
Acute hepatic steatosis in mice by blocking β-oxidation does not reduce insulin sensitivity of very-low-density lipoprotein production
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DOI：
10.1152/ajpgi.00063.2005
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发表时间：
2005-09-01
影响因子：
4.5
通讯作者：
Kuipers, F
中科院分区：
文献类型：
--
作者：
Grefhorst, A;Hoekstra, J;Kuipers, F
肝脏中甘油三酯（TG）的积累通常与肝脏胰岛素抵抗有关。我们质疑药物阻断β-氧化诱导的急性肝脂肪变性是否会影响肝脏胰岛素敏感性，即胰岛素介导的VLDL产生抑制以及胰岛素诱导的磷脂酰肌醇3激酶（PI3激酶）和PKB激活。肉毒碱棕榈酰转移酶 1 (CPT1) 抑制剂十四烷基缩水甘油酸 (TDGA) 用于此目的。雄性C57BL/6J小鼠腹腔注射30 mg/kg TDGA或其溶剂，随后禁食12小时。 CPT1 抑制导致严重的微泡性肝脂肪变性（19.9 +/- 8.3 与 112.4 +/- 25.2 nmol TG/mg 肝脏，对照与治疗组，P < 0.05），血浆非酯化脂肪酸（0.68 +/- 0.25 与 1.21 +/- 0.41 mM，P < 0.05）和血浆 TG 升高（0.39 +/- 0.16 与 0.60 +/- 0.10 mM，P < 0.05）浓度。 VLDL-TG 产生率不受 CPT1 抑制的影响（74.9 +/- 15.2 vs. 79.1 +/- 12.8 mu mol TG center dot kg(-1)center dot min(-1)，对照与治疗组），尽管治疗组小鼠分泌较大的 VLDL 颗粒（59.3 +/- 3.6 vs. 66.6 +/- 4.5 nm 直径，P < 0.05）。在血糖正常的条件下输注胰岛素可将对照小鼠和治疗小鼠的 VLDL 生成率分别抑制 43% 和 54%，并形成更小的 VLDL 颗粒（直径为 51.2 +/- 2.5 和 53.2 +/- 2.8 nm）。 TDGA 治疗不影响胰岛素诱导的胰岛素受体底物 (IRS)1 和 IRS2 相关 PI3 激酶活性和 PKB 磷酸化。总之，药物抑制β-氧化引起的急性肝脂肪变性与肝脏胰岛素敏感性降低无关，表明肝细胞脂肪含量本身与胰岛素抵抗没有因果关系。
Accumulation of triglycerides (TG) in the liver is generally associated with hepatic insulin resistance. We questioned whether acute hepatic steatosis induced by pharmacological blockade of beta-oxidation affects hepatic insulin sensitivity, i.e., insulin-mediated suppression of VLDL production and insulin-induced activation of phosphatidylinositol 3-kinase (PI3-kinase) and PKB. Tetradecylglycidic acid (TDGA), an inhibitor of carnitine palmitoyl transferase-1 (CPT1), was used for this purpose. Male C57BL/6J mice received 30 mg/kg TDGA or its solvent intraperitoneally and were subsequently fasted for 12 h. CPT1 inhibition resulted in severe microvesicular hepatic steatosis (19.9 +/- 8.3 vs. 112.4 +/- 25.2 nmol TG/mg liver, control vs. treated, P < 0.05) with elevated plasma nonesterified fatty acid (0.68 +/- 0.25 vs. 1.21 +/- 0.41 mM, P < 0.05) and plasma TG (0.39 +/- 0.16 vs. 0.60 +/- 0.10 mM, P < 0.05) concentrations. VLDL-TG production rate was not affected on CPT1 inhibition (74.9 +/- 15.2 vs. 79.1 +/- 12.8 mu mol TG center dot kg(-1)center dot min(-1), control vs. treated) although treated mice secreted larger VLDL particles (59.3 +/- 3.6 vs. 66.6 +/- 4.5 nm diameter, P < 0.05). Infusion of insulin under euglycemic conditions suppressed VLDL production rate in control and treated mice by 43 and 54%, respectively, with formation of smaller VLDL particles (51.2 +/- 2.5 and 53.2 +/- 2.8 nm diameter). Insulin-induced insulin receptor substrate (IRS)1- and IRS2-associated PI3-kinase activity and PKB-phosphorylation were not affected on TDGA treatment. In conclusion, acute hepatic steatosis caused by pharmacological inhibition of beta-oxidation is not associated with reduced hepatic insulin sensitivity, indicating that hepatocellular fat content per se is not causally related to insulin resistance.