Hepatic SEC16B regulates lipid homeostasis by coordinating VLDL secretion and lipid droplet expansion
Wei Lu, Zhiming Zhao, Donald Molina, Huaxun Fan, Ruicheng Shi, Ye Tian, Raja Gopoju, Tiantian Yang, Xinyuan Zhang, Yanqiao Zhang, Kai Zhang, Jaume Amengual, Bo Wang
Wei Lu, Zhiming Zhao, Donald Molina, Huaxun Fan, Ruicheng Shi, Ye Tian, Raja Gopoju, Tiantian Yang, Xinyuan Zhang, Yanqiao Zhang, Kai Zhang, Jaume Amengual, Bo Wang
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Research Article Hepatology Metabolism

Hepatic SEC16B regulates lipid homeostasis by coordinating VLDL secretion and lipid droplet expansion

Abstract

The liver plays a critical role in lipid homeostasis, where lipids are either secreted as VLDLs or stored in lipid droplets (LDs). However, the regulatory mechanisms governing these 2 interconnected processes remain poorly understood. Here, we demonstrate that SEC16B functions as a lipid-responsive regulator in the liver, promoting VLDL secretion and LD expansion to handle lipid flux and maintain lipid homeostasis. Genome-wide association studies have identified SNPs in SEC16B to be highly associated with serum lipid levels in humans. Hepatic Sec16b deficiency decreases serum lipid levels by impairing VLDL secretion via disruption of COPII-mediated intracellular trafficking and through mechanisms partially independent of microsomal triglyceride transfer protein–mediated ApoB lipidation. SEC16B partially localizes at ER-LD contact sites and promotes LD expansion by facilitating the targeting of ER proteins to LDs. More importantly, suppression of Sec16b dramatically lowers serum lipid levels and reduces atherosclerotic lesion size in Ldlr null mice. These data reveal a mechanism that coordinates VLDL and LD metabolism and suggest SEC16B as a potential therapeutic target for atherosclerosis treatment.

Authors

Wei Lu, Zhiming Zhao, Donald Molina, Huaxun Fan, Ruicheng Shi, Ye Tian, Raja Gopoju, Tiantian Yang, Xinyuan Zhang, Yanqiao Zhang, Kai Zhang, Jaume Amengual, Bo Wang

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Figure 5

SEC16B controls LD expansion in the liver.

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SEC16B controls LD expansion in the liver. (A) Representative H&E st...
(A) Representative H&E staining of livers from control (F/F) and LKO mice fasted for 16 hours (n = 4). Scale bars: 100 μm. (B and C) Representative electron microscopy (EM) images and quantification of LD diameter in the livers of male control (F/F) and LKO mice fasted for 16 hours (n = 3). Scale bars: 6 μm. (D and E) Percentage of giant LDs (diameter > 2 μm) and the relative frequency of LD size in the livers of male control (F/F) and LKO mice fasted for 16 hours. (F) Representative H&E staining of livers from 8-week-old male control (F/F) and LKO mice fed an HFD, HCD, and WD for 6–12 weeks (n = 3). Scale bars: 200 μm. (G–I) Representative EM images, quantification, and relative frequency of LD size in the livers of WD-fed male control (F/F) and LKO mice (n = 3). Scale bars: 8 μm. (J–L) Representative images, quantification, and relative frequency of LD size in male WT and Sec16b transgenic (Tg) primary hepatocytes treated with 200 μM OA (n = 3). Scale bars: 20 μm. (M–O) Representative images, quantification, and relative frequency of LD size in shCON and shSEC16B Huh7 cells treated with 200 μM OA (n = 3). Scale bars: 10 μm. Values are presented as mean ± SEM or as violin plots. Statistical analysis was performed with 2-tailed Student’s t test (D) or Mann-Whitney test (C, H, K, and N). ****P < 0.0001.