How GLP-1 RAs May Reduce Liver Fat in MASLD, With Takashi Miki, MD, PhD

In the phase 3 ESSENCE trial of metabolic dysfunction-associated steatohepatitis (MASH), semaglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist, resolved steatohepatitis without worsening fibrosis at 72 weeks.¹ Resolution occurred in 62.9% of 534 patients receiving semaglutide vs 34.3% of 266 receiving placebo (P < .001).¹ A preclinical study from Chiba University, published in Cell Reports, examines how GLP-1 signaling reduces liver fat, with implications for metabolic dysfunction-associated steatotic liver disease (MASLD).²,³

The work centers on peroxisome proliferator-activated receptor α (PPARα), a nuclear receptor which switches on genes for fatty acid breakdown in the liver.² The investigators found the bile acid hyodeoxycholic acid (HDCA) reduced liver fat in mice by activating PPARα through 2 routes: invariant natural killer T (iNKT) cells, an immune population in the liver, and GLP-1.² “Both HDCA and the GLP-1 receptor agonist liraglutide exhibited potent anti-steatotic effects in mice in a PPARα-dependent manner,” Takashi Miki, MD, PhD, dean of the Graduate School of Medicine at Chiba University and the study’s lead investigator, said in a statement.³

To test whether GLP-1 needs the immune route, the team gave liraglutide to normal mice and to mice lacking iNKT cells, PPARα, or the GLP-1 receptor.³ Liraglutide still reduced liver fat in mice without iNKT cells but not in mice without PPARα, indicating GLP-1 acts on liver fat through PPARα independently of the immune route.³

In a written interview with HCPLive, Miki discussed what these findings could mean for how clinicians understand the hepatic effects of GLP-1 receptor agonists. He also outlined the questions to resolve before HDCA or PPARα-targeted strategies reach patients with MASLD and his team’s plans to extend the work to MASH.

Q&A: GLP-1 Receptor Agonists, PPARα, and MASLD

HCPLive: Liraglutide reduced liver fat through PPARα independently of iNKT cells. What could this mean for understanding the hepatic effects of GLP-1 receptor agonists?

Takashi Miki, MD, PhD: In recent years, numerous studies have reported beneficial effects of GLP-1 receptor agonists in patients with MASLD. However, the underlying mechanisms of their hepatic effects remain incompletely understood, particularly because GLP-1 receptors are generally considered to be expressed at very low levels, if at all, in hepatocytes.

Furthermore, previous studies have implicated innate immune cells, including iNKT cells, in the regulation of hepatic steatosis, raising the possibility that GLP-1 receptor agonists might suppress hepatic steatosis by activating iNKT cells. However, our findings argue against this hypothesis. Instead, our results suggest that GLP-1 receptor agonists can exert their anti-steatotic effects independently of iNKT cells, through a mechanism involving PPARα.

This provides a new perspective on the hepatic actions of GLP-1 receptor agonists and suggests that their benefits may involve metabolic pathways beyond their well-established effects on appetite and body weight.

HCPLive: These findings come from mouse models. What questions need answering before HDCA or PPARα-targeted strategies could be tested in patients with MASLD?

Takashi Miki, MD, PhD: Our present study demonstrated the protective effects of HDCA against high-fat diet-induced hepatic steatosis in mice and elucidated some of the underlying mechanisms. However, MASLD encompasses a broad spectrum of liver diseases, ranging from simple steatosis to more advanced conditions such as metabolic dysfunction-associated steatohepatitis (MASH). Therefore, an important next step will be to determine whether HDCA can also prevent or ameliorate MASH and its potential progression to hepatocellular carcinoma (HCC).

We also need to establish the safety, efficacy, and mechanisms of action of HDCA in more advanced disease models before considering its potential clinical application.

HCPLive: What are the next steps for your research, and what do you hope clinicians take away from this work?

Takashi Miki, MD, PhD: As mentioned in my response to the previous question, we would like to extend our research to MASH, a more advanced stage of MASLD. Another important finding of our study was that the anti-steatotic effect of liraglutide was abolished in PPARα-deficient mice. This suggests that PPARα signaling plays an important role in mediating the beneficial hepatic effects of GLP-1 receptor agonists.

Based on these findings, we believe that combining GLP-1 receptor agonists with PPARα activators could represent a promising therapeutic strategy for MASLD. We hope that our findings will encourage further research into the interaction between incretin signaling and hepatic lipid metabolism, and ultimately contribute to the development of more effective treatments for MASLD.

Editor’s Note: This transcript has been edited for grammar and clarity using artificial intelligence tools. Miki doesn’t report relevant disclosures.

References

1. Sanyal AJ, Newsome PN, Kliers I, et al. Phase 3 trial of semaglutide in metabolic dysfunction–associated steatohepatitis. N Engl J Med. 2025;392(21):2089-2099. doi:10.1056/NEJMoa2413258

2. Lee E, et al. Hyodeoxycholic acid suppresses hepatic steatosis in a PPARα-dependent manner via distinct GLP-1- and iNKT cell-mediated pathways. Cell Rep. 2026;45(8):117822. doi:10.1016/j.celrep.2026.117822

3. Chiba University. A bile acid shows potential for reducing liver fat. Published September 17, 2026. Accessed October 13, 2026. https://www.chiba-u.ac.jp/e/news/research/a_bile_acid_shows_potential_for_reducing_liver_fat.html