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首页> 外文期刊>American Journal of Physiology >Acute hepatic steatosis in mice by blocking beta-oxidation does not reduce insulin sensitivity of very-low-density lipoprotein production.
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Acute hepatic steatosis in mice by blocking beta-oxidation does not reduce insulin sensitivity of very-low-density lipoprotein production.

机译：通过阻断β-氧化引起的小鼠急性肝脂肪变性不会降低极低密度脂蛋白产生的胰岛素敏感性。

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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 mumol TG.kg(-1).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.
机译：肝脏中甘油三酸酯（TG）的积累通常与肝胰岛素抵抗相关。我们质疑通过药理性阻断β-氧化引起的急性肝脂肪变性是否会影响肝胰岛素敏感性，即胰岛素介导的VLDL产生抑制和胰岛素诱导的磷脂酰肌醇3-激酶（PI3-激酶）和PKB活化。为此，使用了肉碱棕榈酰转移酶-1（CPT1）的抑制剂十四烷基缩水甘油酸（TDGA）。雄性C57BL / 6J小鼠腹膜内接受30 mg / kg TDGA或其溶剂，随后禁食12 h。 CPT1抑制导致严重的微囊性肝脂肪变性（19.9 +/- 8.3 vs. 112.4 +/- 25.2 nmol TG / mg肝脏，对照组与治疗组相比，P <0.05），血浆非酯化脂肪酸升高（0.68 +/- 0.25 vs. 1.21 +/- 0.41 mM，P <0.05）和血浆TG（0.39 +/- 0.16 vs.0.60 +/- 0.10 mM，P <0.05）浓度。 VLDL-TG的产生速率不受CPT1抑制的影响（74.9 +/- 15.2 vs. 79.1 +/- 12.8 mumol TG.kg（-1）.min（-1），对照vs.治疗），尽管治疗的小鼠分泌了更大的VLDL颗粒（直径为59.3 +/- 3.6 vs.66.6 +/- 4.5 nm，P <0.05）。在正常血糖条件下输注胰岛素可使对照组和治疗组小鼠的VLDL产生率分别降低43％和54％，并形成较小的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相关的PI3激酶活性和PKB磷酸化。总之，由药理作用抑制β-氧化引起的急性肝脂肪变性与降低的肝胰岛素敏感性无关，表明肝细胞脂肪含量本身与胰岛素抵抗没有因果关系。

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