Glucagon-like peptide 1 decreases lipotoxicity in non-alcoholic steatohepatitis.
Glucagon-like peptide 1 decreases lipotoxicity in non-alcoholic steatohepatitis.
复制标题
DOI：
10.1016/j.jhep.2015.08.038
复制
发表时间：
2016-02
影响因子：
25.7
通讯作者：
Tomlinson JW
中科院分区：
文献类型：
--
作者：
Armstrong MJ;Hull D;Guo K;Barton D;Hazlehurst JM;Gathercole LL;Nasiri M;Yu J;Gough SC;Newsome PN;Tomlinson JW
胰岛素抵抗和脂毒性是非酒精性脂肪性肝炎（NASH）的特征性表现。胰高血糖素样肽-1（GLP-1）类似物已被批准用于治疗2型糖尿病，但在NASH中尚无前瞻性实验数据。本研究确定了长效GLP-1类似物利拉鲁肽对经活检证实的NASH患者器官特异性胰岛素敏感性、肝脏脂质处理和脂肪功能障碍的影响。在一项双盲、随机化、安慰剂对照试验（ClinicalTrials. gov-NCT 01237119）的机制部分中，14例患者随机接受1.8 mg利拉鲁肽或安慰剂治疗12周。患者接受了成对的高胰岛素血症正常钳夹、稳定同位素示踪剂、脂肪微透析和血清脂肪细胞因子/代谢谱分析。在原代人肝细胞上进行脂质通量的体外同位素实验。利拉鲁肽降低了BMI（−1.9 vs +0.04 kg/m2; p <0.001）、HbA 1c（−0.3 vs +0.3%; p <0.01）、胆固醇-LDL（−0.7 vs +0.05 mmol/L; p <0.01）、ALT（−54 vs −4.0 IU/L; p <0.01）和血清瘦素、脂联素和CCL-2（均p <0.05）。利拉鲁肽增加肝脏胰岛素敏感性（低剂量胰岛素对肝脏内源性葡萄糖产生的抑制率为-9.36% vs.-2.54%; p <0.05）。利拉鲁肽增加了脂肪组织胰岛素敏感性，增强了胰岛素抑制脂解的能力，无论是在整体上（最大限度地抑制血清非酯化脂肪酸的1/2所需的胰岛素为-24.9 pmol/L vs. +54.8 pmol/L; p <0.05），还是在皮下脂肪组织中（p <0.05）。此外，利拉鲁肽可降低体内肝脏新生脂肪生成（−1.26 vs. +1.30%; p <0.05）; GLP-1受体激动剂对原代人肝细胞的作用证实了这一发现（与未给药对照相比，脂肪生成降低24.6%; p <0.01）。利拉鲁肽可降低NASH发病机制中关键代谢器官的代谢功能障碍、胰岛素抵抗和脂毒性。利拉鲁肽可能为NASH的疾病改善干预提供潜力。
Insulin resistance and lipotoxicity are pathognomonic in non-alcoholic steatohepatitis (NASH). Glucagon-like peptide-1 (GLP-1) analogues are licensed for type 2 diabetes, but no prospective experimental data exists in NASH. This study determined the effect of a long-acting GLP-1 analogue, liraglutide, on organ-specific insulin sensitivity, hepatic lipid handling and adipose dysfunction in biopsy-proven NASH. Fourteen patients were randomised to 1.8 mg liraglutide or placebo for 12-weeks of the mechanistic component of a double-blind, randomised, placebo-controlled trial (ClinicalTrials.gov-NCT01237119). Patients underwent paired hyperinsulinaemic euglycaemic clamps, stable isotope tracers, adipose microdialysis and serum adipocytokine/metabolic profiling. In vitro isotope experiments on lipid flux were performed on primary human hepatocytes. Liraglutide reduced BMI (−1.9 vs. +0.04 kg/m2; p <0.001), HbA1c (−0.3 vs. +0.3%; p <0.01), cholesterol-LDL (−0.7 vs. +0.05 mmol/L; p <0.01), ALT (−54 vs. −4.0 IU/L; p <0.01) and serum leptin, adiponectin, and CCL-2 (all p <0.05). Liraglutide increased hepatic insulin sensitivity (−9.36 vs. −2.54% suppression of hepatic endogenous glucose production with low-dose insulin; p <0.05). Liraglutide increased adipose tissue insulin sensitivity enhancing the ability of insulin to suppress lipolysis both globally (−24.9 vs. +54.8 pmol/L insulin required to ½ maximally suppress serum non-esterified fatty acids; p <0.05), and specifically within subcutaneous adipose tissue (p <0.05). In addition, liraglutide decreased hepatic de novo lipogenesis in vivo (−1.26 vs. +1.30%; p <0.05); a finding endorsed by the effect of GLP-1 receptor agonist on primary human hepatocytes (24.6% decrease in lipogenesis vs. untreated controls; p <0.01). Liraglutide reduces metabolic dysfunction, insulin resistance and lipotoxicity in the key metabolic organs in the pathogenesis of NASH. Liraglutide may offer the potential for a disease-modifying intervention in NASH.