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
View: Text | PDF
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

×

Figure 1

Association between SNPs in SEC16B gene and plasma cholesterol in humans and its expression regulation.

Options: View larger image (or click on image) Download as PowerPoint
Association between SNPs in SEC16B gene and plasma cholesterol in humans...
(A) Regional plot of SEC16B associated with plasma total cholesterol and LDL-C levels in humans. Red dashed line indicates the threshold of genome-wide significance (P = 5 × 10–8). (B) eQTL studies showing a highly significant correlation between rs6682862 and SEC16B expression in the liver. (C) Luciferase activity of SEC16B promoter carrying G and A alleles in HEK293 cells (n = 4). (D) Enrichment analysis showing candidate transcription factors that may bind to 1,000 bp up- or downstream of Sec16b transcription start sites in mouse livers. Data are from ChIP-Atlas. (E) RNA-seq, DNase-seq, ATAC-seq, and HNF4A ChIP-seq reads at the SEC16B locus of human and mouse liver. Red boxes indicate HNF4A binding peaks from ChIP-seq data. (F and G) Sec16b mRNA levels in fetal (F) and adult male (G) Hnf4a-KO mouse livers (n = 3 in F; n = 6–8 in G). 8-week-old mice were fed an HFCF diet for 20 weeks (G). (H) Sec16b mRNA levels in male HNF4A overexpression mouse livers (n = 8). 8-week-old mice were fed an HFCF diet for 20 weeks. (I) Luciferase activity of SEC16B promoter carrying G and A alleles in control and HNF4A-overexpressing HEK293 cells (n = 4). (J) Sec16b mRNA levels in the livers of ad lib fed, fasted, and refed male mice (n = 5–7). 8-week-old mice were fasted for 12 hours or fasted for 12 hours and refed HCD for 12 hours. (K) Sec16b mRNA levels in the livers of 8 weeks old male mice fed chow or HFD for 12 weeks (n = 6–7). (L) SEC16B expression in lean and obese hepatocytes. Data are from Liver Cell Atlas. (M) SEC16B expression in the livers of healthy donors and patients with MASLD. (N) Sec16b mRNA levels in mouse primary hepatocytes treated with BSA and 200 μM oleic acid (OA). (O) SEC16B mRNA levels in Huh7 cells treated with BSA and 200 μM OA. Values are presented as mean ± SEM or as violin plots. Statistical analysis was performed with 2-tailed Student’s t test (C, F–H, K, and M–O), 1-way ANOVA (J), and 2-way ANOVA (I). *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001.