# Fenofibrate Treatment Inhibits Very-Low-Density Lipoprotein Transport Vesicle Formation by Reducing Sar1b Protein Expression

## TL;DR

Fenofibrate reduces VLDL secretion by inhibiting the formation of transport vesicles in liver cells through decreased Sar1B protein expression.

## Contribution

This study reveals a novel mechanism of fenofibrate's lipid-lowering effects by targeting intracellular VLDL trafficking.

## Key findings

- Fenofibrate treatment significantly reduces VLDL secretion in HepG2 cells.
- Fenofibrate alters VLDL triglyceride localization, delaying transport through the endoplasmic reticulum and Golgi.
- Fenofibrate decreases Sar1B protein expression, a key factor in VLDL transport vesicle formation.

## Abstract

Dyslipidemia is a well-known risk factor in the development and progression of atherosclerosis. VLDL plays a crucial role in maintaining lipid homeostasis; however, even minor fluctuations in its production, intracellular trafficking, and secretion can contribute to the progression of atherosclerosis. Fenofibrate is an FDA-approved drug that effectively lowers plasma triglycerides and VLDL-associated cholesterol while simultaneously increasing HDL levels. Although fenofibrate is a known PPARα agonist with several proposed mechanisms for its lipid-altering effects, its impact on the intracellular trafficking of VLDL has not yet been investigated. We observed that treatment of HepG2 cells with 50 µM of fenofibrate resulted in a significant reduction in VLDL secretion, as evidenced by a significant decrease in the secretion of 3H-labeled TAG, fluorescent TAG, and ApoB100 protein into the media. Using confocal microscopy to monitor VLDL intracellular trafficking, we observed a distinct change in VLDL triglyceride localization, suggesting delayed transport through the endoplasmic reticulum and Golgi. An immunoblot analysis revealed a decrease in Sar1B protein expression, a key regulator of COPII protein recruitment, which is essential for VTV formation and intracellular VLDL trafficking, the rate-limiting step in VLDL secretion. Our data reveal a novel mechanism by which fenofibrate alters the lipid profile by interfering with intracellular VLDL trafficking in hepatocytes.