What question did this study set out to answer?

This research investigates the metabolic role of TLR2 in lipid handling and its potential as a therapeutic target for MASLD.

June 7, 2026

2475-P: TLR2-Selective Agonism Reverses and Prevents Hepatic Steatosis in Diet-Induced Obese Mice

Key Points

This research investigates the metabolic role of TLR2 in lipid handling and its potential as a therapeutic target for MASLD.
Male C57BL/6J and TLR2 knockout mice were fed a high-fat diet for 16 weeks.
Mice were treated with TLR2 agonist Pam3CSK4 to assess effects on hepatic steatosis and metabolic outcomes.
Analyses included RNA-seq, qRT-PCR, FACS, histology, and human liver biopsies for translational validation.
TLR2 deficiency caused increased hepatic steatosis and insulin resistance, independent of inflammation.
Pam3CSK4 treatment in WT mice reversed hepatic steatosis, improved glucose tolerance, and induced hepatic lipid oxidation genes.
In TLR2KO mice, the metabolic benefits of Pam3CSK4 treatment were absent, confirming the essential role of TLR2.

Abstract

Introduction and Objective: Metabolic dysfunction-associated steatotic liver disease (MASLD) results from dysregulated hepatic lipid handling. Here, we uncover an inflammation independent metabolic role for Toll-like receptor 2 (TLR2) that protects against hepatic steatosis and establish proof of concept for its therapeutic potential. Methods: C57BL/6J (WT) and TLR2 knockout (KO) male mice were fed a high-fat diet (HFD) to induce MASLD for 16 weeks. TLR2KO and WT mice were then treated with Pam3CSK4. Hepatic steatosis, plasma lipid profiles, and glucose tolerance (GT) were assessed. In vivo and in vitro samples were examined by RNA-seq, qRT-PCR, FACS, histology, ChIP-qPCR, W-blot, and siRNA transfection. Human liver biopsies from patients with MASLD were used for translational validation. Results: TLR2 deficiency led to obesity, insulin resistance, and marked hepatic steatosis that occurred independently of hepatic inflammation. Mechanistically, loss of TLR2 increased hepatocyte lipid accumulation via a cell-autonomous pathway involving upregulation of PPARγ-CD36. Genetic deletion of PPARγ or CD36 mitigated lipid accumulation induced by TLR2 loss. Activation of TLR2 in mice with the selective agonist Pam3CSK4 suppressed hepatic PPARγ-CD36 signaling, reduced lipid uptake and storage, and prevented steatosis. In obese WT mice, Pam3CSK4 treatment reversed established hepatic steatosis, improved GT, reduced TG, increased plasma HDL-C, and enhanced lipoprotein export, accompanied by induction of hepatic lipid oxidation and export genes and proteins (Ppara, Cpt1a, Acox1, ApoB, and Mttp). These metabolic benefits were absent in TLR2KO mice, confirming strict TLR2 dependency. Human MASLD livers exhibited low TLR2, increased fat, and elevated PPARγ-CD36. Conclusion: TLR2 exerts a protective role in hepatic lipid homeostasis by suppressing the PPARγ-CD36 lipid uptake axis while promoting lipid oxidation and export. Activation of TLR2 by Pam3CSK4 reverses hepatic steatosis in preclinical murine models, highlighting its therapeutic promise for MASLD. Disclosure S. Kochumon: None. F. Alrashed: None. F. Alzaid: None. F. Bahman: None. N. Benobaid: None. T.K. Jacob: None. R. Nizam: None. N. Akhter: None. A. Al Madhoun: None. F. Al-Mulla: None. E. Rosen: Consultant; Ended; Novartis AG. Research Support; Current; Roche Pharmaceuticals, Alnylam Pharmaceuticals, Inc. R. Ahmad: None. Funding Kuwait Foundation for the Advancement of Sciences (KFAS). Grant# RA AM 2023-021

AIに質問

Bookmark

Cite This Study

Kochumon et al. (Fri,) studied this question.

synapsesocial.com/papers/6a250c7d7def13d035e1cb0c https://doi.org/https://doi.org/10.2337/db26-2475-p

AIに質問

Bookmark