Department of Endocrinology and Metabolism, The Affiliated Hospital of Qingdao University, Qingdao, 266000, Shandong, China; Department of Endocrinology and Metabolism, Rongcheng People's Hospital, Rongcheng, 264300, Shandong, China.
Department of Endocrinology and Metabolism, The Affiliated Hospital of Qingdao University, Qingdao, 266000, Shandong, China.
Biochem Biophys Res Commun. 2020 Aug 20;529(2):480-486. doi: 10.1016/j.bbrc.2020.06.055. Epub 2020 Jul 2.
Primary Hypertriglyceridemia refers to a loss-of-function genetic defect which prevents the triglyceride (TG) in chylomicrons (CM) from lipolysis, leading to the accumulation of TG. The mutation of lipoprotein lipase (LPL) gene has been recognized as the main cause of primary hypertriglyceridemia. Recently, a new LPL gene mutation p.C310R(c. T928C) was identified in a family with hypertriglyceridemia. The proband was manifested by severe hypertriglyceridemia and diabetes. Skeletal muscle is the major LPL-synthesizing tissue and insulin response target tissue. However, little is known about the effects of LPL gene mutation on skeletal muscle. This study is intended to observe the effects of LPL-C310R mutation on glycolipid metabolism and skeletal muscle. We found that a significantly decreased LPL plasma concentration, activity and the expression levels in skeletal muscle were observed in Lpl mice comparing to wild type mice. Those mutant mice also exhibited increased fasting plasma TG, free fat acids (FFA) and insulin, as well as FFA in muscle, and decreased glucose tolerance. Enhanced expression of BIP and elevated phosphorylation of IRE1α were observed in skeletal muscle, suggesting increased endoplasmic reticulum stress (ERS). Consistent with this, increased phosphorylation of JNK was also observed. Meanwhile, remarkably enhanced phosphorylation of IRS-1 (Ser307) and decreased phosphorylation of AKT were observed in skeletal muscle of mutant mice, suggesting impaired insulin signaling. Significant lipid deposition and morphological changes in endoplasmic reticulum and mitochondria were observed in the skeletal muscle of mutant mice but not in wild type control. Results demonstrate Lpl C310R mutation caused impaired glucose tolerance, ER stress and impaired insulin signaling in skeletal muscle.
原发性高甘油三酯血症是指一种功能丧失的遗传缺陷，它阻止乳糜微粒（CM）中的甘油三酯（TG）进行脂解，导致 TG 的积累。脂蛋白脂肪酶（LPL）基因突变已被认为是原发性高甘油三酯血症的主要原因。最近，在一个高甘油三酯血症的家族中发现了一种新的 LPL 基因突变 p.C310R（c. T928C）。先证者表现为严重的高甘油三酯血症和糖尿病。骨骼肌是 LPL 合成的主要组织和胰岛素反应的靶组织。然而，关于 LPL 基因突变对骨骼肌的影响知之甚少。本研究旨在观察 LPL-C310R 突变对糖脂代谢和骨骼肌的影响。我们发现与野生型小鼠相比，Lpl 小鼠的血浆 LPL 浓度、活性和骨骼肌表达水平明显降低。这些突变小鼠还表现出空腹血浆 TG、游离脂肪酸（FFA）和胰岛素增加，肌肉 FFA 减少，葡萄糖耐量降低。骨骼肌中 BIP 的表达增强，IRE1α 的磷酸化增加，提示内质网应激（ERS）增加。与此一致，JNK 的磷酸化也明显增加。同时，还观察到突变小鼠骨骼肌中 IRS-1（Ser307）的磷酸化显著增强，AKT 的磷酸化减少，提示胰岛素信号受损。突变小鼠骨骼肌中观察到明显的脂质沉积和内质网及线粒体的形态变化，但在野生型对照组中没有观察到。结果表明，Lpl C310R 突变导致骨骼肌葡萄糖耐量受损、内质网应激和胰岛素信号受损。
