Hepatic Phospholipid Remodeling Modulates Insulin Sensitivity and Systemic Metabolism.
Hepatic Phospholipid Remodeling Modulates Insulin Sensitivity and Systemic Metabolism.
复制标题
肝脏磷脂重塑调节胰岛素敏感性和全身代谢。
DOI：
10.1002/advs.202300416
复制
发表时间：
2023-06
期刊：
影响因子：
15.1
通讯作者：
Wang, Bo
中科院分区：
文献类型：
--
作者：
Tian, Ye;Mehta, Kritika;Jellinek, Matthew J.;Sun, Hao;Lu, Wei;Shi, Ruicheng;Ingram, Kevin;Friedline, Randall H.;Kim, Jason K.;Kemper, Jongsook Kim;Ford, David A.;Zhang, Kai;Wang, Bo
肝脏在调节葡萄糖和脂质代谢中起着核心作用。肝脏中异常的胰岛素作用是选择性胰岛素抵抗的主要驱动因素，其中胰岛素无法抑制葡萄糖的产生，但继续激活肝脏中的脂肪生成，导致高血糖和高甘油三酯血症。选择性胰岛素抵抗的潜在机制尚不完全清楚。这里显示，由溶血磷脂酰胆碱酰基转移酶 3 (LPCAT3) 控制的肝膜磷脂组成调节胰岛素信号传导和全身葡萄糖和脂质代谢。高脂饮食 (HFD) 喂养引起的高胰岛素血症会增加肝脏 Lpcat3 表达和膜不饱和度。在 HFD 喂养和遗传 ob/ob 小鼠模型中，肝脏中 Lpcat3 的缺失会改善胰岛素抵抗并减弱脂肪生成。从机制上讲，Lpcat3 缺乏直接促进胰岛素受体内吞作用、信号转导和肝脏葡萄糖产生抑制，并间接增强脂肪组织中成纤维细胞生长因子 21 (FGF21) 的分泌、能量消耗和葡萄糖摄取。这些发现确定肝脏 LPCAT3 和膜磷脂成分是胰岛素敏感性的新型调节剂，并为选择性胰岛素抵抗的发病机制提供了见解。通过消耗 PL 重塑酶 LPCAT3 介导的肝磷脂 (PL) 饱和度，可通过 FGF21 和增加的能量消耗来保护小鼠免受饮食诱导的肥胖。肝脏中 Lpcat3 的消除通过促进胰岛素受体内吞进入早期内体和棕色脂肪组织中的葡萄糖摄取来改善胰岛素敏感性。
The liver plays a central role in regulating glucose and lipid metabolism. Aberrant insulin action in the liver is a major driver of selective insulin resistance, in which insulin fails to suppress glucose production but continues to activate lipogenesis in the liver, resulting in hyperglycemia and hypertriglyceridemia. The underlying mechanisms of selective insulin resistance are not fully understood. Here It is shown that hepatic membrane phospholipid composition controlled by lysophosphatidylcholine acyltransferase 3 (LPCAT3) regulates insulin signaling and systemic glucose and lipid metabolism. Hyperinsulinemia induced by high‐fat diet (HFD) feeding augments hepatic Lpcat3 expression and membrane unsaturation. Loss of Lpcat3 in the liver improves insulin resistance and blunts lipogenesis in both HFD‐fed and genetic ob/ob mouse models. Mechanistically, Lpcat3 deficiency directly facilitates insulin receptor endocytosis, signal transduction, and hepatic glucose production suppression and indirectly enhances fibroblast growth factor 21 (FGF21) secretion, energy expenditure, and glucose uptake in adipose tissue. These findings identify hepatic LPCAT3 and membrane phospholipid composition as a novel regulator of insulin sensitivity and provide insights into the pathogenesis of selective insulin resistance. Hepatic phospholipid (PL) saturation, mediated by depletion of a PL remodeling enzyme LPCAT3, protects mice from diet‐induced obesity through FGF21 and elevated energy expenditure. Ablation of Lpcat3 in the liver improves insulin sensitivity by facilitating insulin receptor endocytosis into early endosomes and glucose uptake in brown adipose tissue.
登录
查看更多内容
影响因子：
29
作者：
Lin HV;Accili D
通讯作者：
Accili D
影响因子：
8
作者：
Luukkonen, Panu K.;Nick, Auli;Yki-Javinen, Hannele
通讯作者：
Yki-Javinen, Hannele
DOI：
10.1038/nrm.2017.89
发表时间：
2018-01
期刊：
Nature reviews. Molecular cell biology
影响因子：
--
作者：
Haeusler RA;McGraw TE;Accili D
通讯作者：
Accili D
影响因子：
16.6
作者：
Kim B;Pang HB;Kang J;Park JH;Ruoslahti E;Sailor MJ
通讯作者：
Sailor MJ
影响因子：
4.8
作者：
DeMarco, Vincent G.;Ford, David A.;Sowers, James R.
通讯作者：
Sowers, James R.