Lu and colleagues identified SEC16B as a regulator of both VLDL and LD metabolism (5). Previous GWAS identified an association between the minor allele of a SNP (rs6682862, chr1:177969302) located in the promoter region of SEC16B and serum cholesterol levels (17, 18) and determined that SEC16B SNPs are strongly associated with obesity and BMI (19). Using this information, the authors established that this minor SEC16B allele is correlated with increased hepatic expression of SEC16B. In vitro and in vivo assays revealed that HNF4A is a key regulator in SEC16B expression and showed that SEC16B was upregulated in response to FAs and lipids. Lu and colleagues generated whole-body and liver-specific Sec16b-KO mouse models, both of which exhibited lower serum TG levels. Additionally, the liver-specific Sec16b-KO model showed lipid accumulation that was not observed in whole-body Sec16b-KO mice.

Based on these findings, Lu et al. hypothesized that loss of Sec16b may block VLDL secretion from the liver. The authors discovered that SEC16B regulates ApoB secretion, which appears to be partially independent from MTTP-mediated initial lipidation. Subsequent studies indicated that SEC16B regulated VLDL production by mediating both ApoB lipidation during the generation of VLDL and trafficking nascent VLDL to the Golgi in liver cells. In studies to elucidate the molecular mechanisms by which SEC16B regulates VLDL secretion, the authors showed that knockdown of SEC16B in human hepatocytes impaired the interaction between the COPII components SEC13 and SEC31A. This disruption of COPII assembly altered ApoB secretion, which indicates that SEC16B is critical for COPII-mediated VLDL trafficking. Because impaired VLDL formation leads to LD generation, the authors then assessed LD formation and showed that SEC16B was necessary to regulate hepatic LD size in human hepatocytes; however, SEC16B deficiency led to smaller LD size. Given that SEC16B deficiency impaired VLDL secretion and is expected to produce larger LDs, the smaller LDs observed in liver-specific SEC16B-KO hepatocytes are likely the result of a mechanism independent of impaired VLDL secretion. Through a series of sophisticated studies in control and in liver-specific SEC16B-KO hepatocytes, the authors showed that SEC16B partially localized to ER-LD contact sites and regulated LD expansion by modulating the translocation of LD-associated ER proteins (Figure 1). Finally, they provide clinical implications for their findings in Ldlr–/– models of atherosclerosis, showing that: (a) constitutive Sec16b deficiency reduced atherosclerosis without causing lipotoxicity, (b) acute deletion of hepatic Sec16b slowed down the progression of atherosclerosis without significant effects on the liver, and (c) SEC16B is not a key player in the development of metabolic dysfunction–associated steatohepatitis because hepatic Sec16b deletion did not alter the progression of this disorder in mouse models.

These studies are innovative and will advance the field considerably. Lipid storage can be detrimental to the liver and lead to fatty liver disease, so regulation of lipid secretion in the form of TG-rich VLDLs to supply the peripheral tissue is an important, yet understudied, physiological process. The findings by Lu et al. provide a mechanism by which these two processes communicate with each other. They demonstrated that SEC16B regulates hepatic lipid metabolism that increases both VLDL secretion and the expansion of LDs. By doing so, SEC16B regulates lipid flux and maintains lipid homeostasis in the liver and in the bloodstream. Most importantly, deletion of SEC16B in preclinical models led to a reduction in serum lipid levels and decreased the likelihood of developing an atherosclerotic plaque. Given that atherosclerotic vascular disorders are now the most common cause of death in the world, targeting SEC16B may become an important therapeutic approach to reduce the incidence of such a common disease.

These studies complement another recent publication on the role of SEC16B in hepatic lipid homeostasis (20). Wang et al. showed that SEC16B plays a critical role in ApoB-containing lipoproteins from the liver and is an important regulator of COPII machinery. Through a series of bioinformatic, genome-wide correlation, tissue-specific expression, and single-cell analyses, they identified SEC16B as a selective regulator of lipid transport and lipoprotein generation. They then employed functional studies and prediction analysis using AI to show that SEC16B puts a brake on the COPII-mediated role in lipoprotein export. Mining clinical databases, they then showed that SEC16B is linked to metabolic diseases, and its expression is regulated by HNF4A. Finally, they showed that SEC16B deletion in mice protects against atherosclerosis formation and decreases serum levels of ApoB, TG, and cholesterol. These data support Lu et al.’s findings and indicate the SEC16B is a regulator of lipoprotein (VLDL) export and may be a potential target for therapy in atherosclerosis and metabolic disorders.