Faculty, Staff and Student Publications

Language

English

Publication Date

1-29-2026

Journal

Journal of Lipid Research

DOI

10.1016/j.jlr.2026.100988

PMID

41616827

PMCID

PMC12945629

PubMedCentral® Posted Date

1-29-2026

PubMedCentral® Full Text Version

Post-print

Abstract

VLDLs are crucial for maintaining liver and whole-body lipid homeostasis. Limited knowledge exists regarding the lipidation process of VLDL. Endoplasmic reticulum (ER) luminal lipid droplets (LLDs) have been suggested to provide lipids for VLDL lipidation and maturation. Seipin, an integral membrane protein of the ER, plays key roles in the formation of cytoplasmic LDs (CLDs) and adipocyte differentiation. Surprisingly, seipin is hardly detectable in hepatocytes. Given the critical contribution of seipin in forming CLDs, we hypothesize that the absence of seipin in hepatocytes might ensure the proper formation of LLDs and the lipidation and assembly of VLDLs. To explore the functional interactions between CLDs, LLDs, and VLDLs, we generated liver-specific human seipin (hSeipin) overexpression (adeno-associated virus [AAV]-hSeipin) mice using AAV. We examined hepatic lipid accumulation, plasma lipid levels, VLDL lipidation, and liver pathology using biochemical, histological, and electron microscopy techniques. Liver-specific overexpression of seipin resulted in increased accumulation of CLDs in hepatocytes, accompanied by reduced plasma triacylglycerol and cholesterol levels. VLDL lipidation was severely impaired in AAV-hSeipin mice. When subjected to a high-fat, high-cholesterol diet, AAV-hSeipin mice developed more severe hepatic inflammation and fibrosis. These findings suggest that enhanced formation of CLDs driven by seipin may channel lipid storage toward the cytoplasm of hepatocytes, thereby impeding the biogenesis of LLDs and causing defective VLDL lipidation in the ER lumen. Our results thus provide important new insights into the connection between the biogenesis of CLDs and LLDs as well as VLDL assembly.

Keywords

seipin, lipid droplets, VLDL, liver steatosis, fibrosis, lipid metabolism

Published Open-Access

yes

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