Chen Chia-Hui, Ho Sin-Ni, Hu Po-An, Kou Yu Ru, Lee Tzong-Shyuan
Graduate Institute and Department of Physiology, College of Medicine, National Taiwan University, Taipei, Taiwan.
Department of Physiology, School of Medicine, National Yang-Ming University, Taipei, Taiwan.
J Food Drug Anal. 2020 Jun 15;28(2):206-216. doi: 10.38212/2224-6614.1055.
Sorbic acid (SA) is one of the most commonly used food preservatives worldwide. Despite SA having no hepatotoxicity at legal dosages, its effect on hepatic lipid metabolism is still unclear. We investigated the effect of SA on hepatic lipid metabolism and its mechanism of action in C57BL/6 mice. Daily treatment with SA (1 g/kg in diet) for 4 weeks did not alter the body weight, organ weight, and blood lipids in mice. However, hepatic lipid accumulation, particularly that of triglycerides, fatty acids, and glycerol, but not cholesteryl ester and free cholesterol, was increased with SA treatment. Mechanistically, SA decreased the expression of proteins related to de novo fatty acid lipogenesis, fatty acid internalization, and very low-density lipoprotein (VLDL) secretion-related pathways, including sterol regulatory element-binding proteins, acetyl-coA carboxylase, fatty acid synthase, liver fatty acid-binding protein, CD36, and apolipoprotein E. In contrast, SA increased the expression of diacylglycerol O-acyltransferase 2, the key enzyme for triacylglycerol synthesis. Moreover, SA downregulated the protein expression of autophagy-related and β-oxidation-related pathways, the two major metabolic pathways for lipid metabolism, including LC-3, beclin-1, autophagy related protein 5 (ATG-5) and ATG-7, acyl-CoA synthetase long chain family member 1, carnitine palmitoyltransferase Iα, peroxisome proliferator-activated receptor α (PPARα), PPARγ, and PPARγ coactivator-1. Collectively, SA deregulates de novo lipogenesis and fatty acid internalization, VLDL secretion, autophagy, and β-oxidation in the liver, leading to impaired lipid clearance and ultimately, resulting in lipid accumulation in the liver.
山梨酸（SA）是全球最常用的食品防腐剂之一。尽管SA在法定剂量下没有肝毒性，但其对肝脏脂质代谢的影响仍不清楚。我们研究了SA对C57BL/6小鼠肝脏脂质代谢的影响及其作用机制。每天用SA（饮食中1 g/kg）处理4周，并未改变小鼠的体重、器官重量和血脂。然而，SA处理会增加肝脏脂质积累，尤其是甘油三酯、脂肪酸和甘油的积累，但不会增加胆固醇酯和游离胆固醇的积累。从机制上讲，SA降低了与从头脂肪酸脂肪生成、脂肪酸内化和极低密度脂蛋白（VLDL）分泌相关途径的蛋白质表达，包括固醇调节元件结合蛋白、乙酰辅酶A羧化酶、脂肪酸合酶、肝脏脂肪酸结合蛋白、CD36和载脂蛋白E。相反，SA增加了甘油二酯O-酰基转移酶2的表达，该酶是三酰甘油合成的关键酶。此外，SA下调了自噬相关和β-氧化相关途径的蛋白质表达，这是脂质代谢的两个主要代谢途径，包括LC-3、贝克林1、自噬相关蛋白5（ATG-5）和ATG-7、酰基辅酶A合成酶长链家族成员1、肉碱棕榈酰转移酶Iα、过氧化物酶体增殖物激活受体α（PPARα）、PPARγ和PPARγ辅激活因子-1。总体而言，SA会破坏肝脏中的从头脂肪生成、脂肪酸内化、VLDL分泌、自噬和β-氧化，导致脂质清除受损，并最终导致肝脏脂质积累。
