Acetoacetate Ameliorates Hepatic Fibrosis by Targeting Peroxisome Proliferator-Activated Receptor Gamma to Restore Lipid Droplets in Activated Hepatic Stellate Cells

TL;DR

Acetoacetate helps reduce liver fibrosis by restoring lipid droplets in liver cells through a key protein called PPARγ.

Contribution

This study reveals a novel mechanism by which acetoacetate inhibits hepatic stellate cell activation via PPARγ regulation.

Findings

Acetoacetate inhibits HSC activation by restoring lipid droplet levels.

PPARγ is a key regulator in this process, as its knockdown worsens fibrosis.

Acetoacetate regulates PPARγ expression, offering a potential therapeutic strategy for HF.

Abstract

Background: Hepatic fibrosis (HF) is a progressive liver disease characterized by the activation of hepatic stellate cells (HSCs) and changes in lipid metabolism. Abnormal ketone body (KD) levels, including acetoacetate (AcAc) and beta-hydroxybutyrate (BHB), have been observed in patients with HF, but the mechanisms linking ketone metabolism to fibrosis progression remain unclear. Objectives: This study aimed to investigate the role of AcAc in modulating HSCs activation and its potential mechanisms in HF. Methods: We examined the effects of AcAc on HSCs activation by Western blot analysis and RT-PCR both in vivo and in vitro. The impact of AcAc on lipid droplet accumulation in HSCs was assessed using total cholesterol (TC), triglyceride (TG), and Retinol (RET) kits, along with Nile Red and Oil Red O staining. RT-PCR screening was performed to analyze the expression of genes involved in lipid droplet formation and lipid metabolism. Results: Our findings show that AcAc inhibited HSCs activation by restoring LD levels. Peroxisome Proliferator-Activated Receptor Gamma (PPARγ) was identified as a key regulator through gene screening. AcAc primarily regulated PPARγ expression, and knocking down PPARγ significantly aggravated HF progression. Conclusions: The ability of AcAc to restore LD levels and regulate PPARγ suggests that it may represent a promising therapeutic strategy for HF by inhibiting HSCs activation.

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