Department of Pharmacology and Physiology, Saint Louis University School of Medicine, St. Louis, MO.
Department of Molecular Biosciences, School of Veterinary Medicine, California National Primate Research Center, and Department of Nutrition, University of California, Davis, CA.
J Lipid Res. 2019 Apr;60(4):805-818. doi: 10.1194/jlr.M089508. Epub 2019 Feb 5.
Dyslipidemia and insulin resistance are significant adverse outcomes of consuming high-sugar diets. Conversely, dietary fish oil (FO) reduces plasma lipids. Diet-induced dyslipidemia in a rhesus model better approximates the pathophysiology of human metabolic syndrome (MetS) than rodent models. Here, we investigated relationships between metabolic parameters and hypertriglyceridemia in rhesus macaques consuming a high-fructose diet (n = 59) and determined the effects of FO supplementation or RNA interference (RNAi) on plasma ApoC3 and triglyceride (TG) concentrations. Fructose supplementation increased body weight, fasting insulin, leptin, TGs, and large VLDL particles and reduced adiponectin concentrations (all < 0.001). In multiple regression analyses, increased plasma ApoC3 was the most consistent and significant variable related to diet-induced hypertriglyceridemia. FO supplementation, which attenuated increases of plasma TG and ApoC3 concentrations, reversed fructose-induced shifts of lipoprotein particle size toward IDL and VLDL, a likely mechanism contributing to beneficial metabolic effects, and reduced hepatic expression of genes regulated by the SREBP pathway, particularly acetyl-CoA carboxylase. Furthermore, RNAi-mediated ApoC3 inhibition lowered plasma TG concentrations in animals with diet-induced hypertriglyceridemia. In summary, ApoC3 is an important independent correlate of TG-rich lipoprotein concentrations in rhesus macaques consuming a high-fructose diet. ApoC3 is a promising therapeutic target for hypertriglyceridemia in patients with MetS and diabetes.
高糖饮食会导致血脂异常和胰岛素抵抗，而食用富含鱼油的饮食则可以降低血浆脂质水平。与啮齿动物模型相比，食源性高血脂症的恒河猴模型更能模拟人类代谢综合征（MetS）的病理生理学。在此，我们研究了摄入高果糖饮食的恒河猴（n = 59）的代谢参数与高甘油三酯血症之间的关系，并确定了鱼油补充或 RNA 干扰（RNAi）对血浆载脂蛋白 C3（ApoC3）和甘油三酯（TG）浓度的影响。果糖的补充增加了体重、空腹胰岛素、瘦素、甘油三酯和大 VLDL 颗粒，同时降低了脂联素浓度（均 < 0.001）。在多元回归分析中，血浆 ApoC3 升高是与饮食诱导的高甘油三酯血症最一致和最显著的相关变量。鱼油的补充减轻了血浆 TG 和 ApoC3 浓度的升高，逆转了果糖引起的脂蛋白颗粒大小向 IDL 和 VLDL 的转移，这可能是其产生有益代谢作用的机制之一，还降低了 SREBP 通路调节基因的肝表达，特别是乙酰辅酶 A 羧化酶。此外，RNAi 介导的 ApoC3 抑制降低了饮食诱导高甘油三酯血症动物的血浆 TG 浓度。总之，ApoC3 是摄入高果糖饮食的恒河猴 TG 丰富的脂蛋白浓度的一个重要独立相关因素。ApoC3 是 MetS 和糖尿病患者高甘油三酯血症的一个有前途的治疗靶点。
