A bile acid shows potential for reducing liver fat

Non-alcoholic fatty liver disease (NAFLD), now known as metabolic dysfunction-associated steatotic liver disease (MASLD), is a common condition that causes excess fat to build up in the liver, affecting about one-quarter of adults worldwide. In some people, this can lead to inflammation and liver cell or hepatocyte injury, triggering the formation of thick, fibrous connective tissue known as fibrosis. Over time, advanced fibrosis can progress to cirrhosis, in which permanent scarring impairs the liver’s normal function. MASLD is often described as a “silent” disease because symptoms may be absent or mild until the disease becomes more advanced.

Hepatic steatosis refers to the initial stage of MASLD, where excess fat gets accumulated in the hepatocytes. Though it is a common metabolic disorder, the mechanistic understanding of the biological pathways involved as well as effective therapeutic strategies remain incompletely understood.

Against this backdrop, a study from Chiba University found that a bile acid, hyodeoxycholic acid (HDCA), helps reduce excess fat accumulation in the liver.

The study was led by Professor Takashi Miki, Dean of the Graduate School of Medicine at Chiba University, Japan, with Dr. Eunyoung Lee as the first author, along with Professor Antonio Vidal-Puig of the MRC Institute of Metabolic Science, University of Cambridge, UK, and other researchers. The paper was made available online on August 7, 2026, and was published in Volume 45, Issue 8 of the journal Cell Reports on August 25, 2026.

“We unexpectedly found that adipose tissue transplantation increased circulating HDCA levels in our diabetic mouse model. This intriguing finding prompted us to investigate HDCA's potential metabolic effects. We found that HDCA treatment prevented high-fat diet-induced hepatic steatosis,” says Prof. Miki.

To investigate the effects of HDCA, the researchers fed mice a high-fat diet and treated them with HDCA. At a 0.25% dose, HDCA reduced blood glucose levels, lowered the amount of triglycerides (fat) stored in the liver, and improved liver function without affecting the mice’s body weight, suggesting that its effects on liver fat were not due to weight loss.

The researchers then investigated how HDCA produced these effects. They found that HDCA increased the activity of PPARα, a protein that controls genes involved in breaking down fatty acids. In mice that lacked this protein, HDCA could no longer prevent fat from building up in the liver.

The researchers then identified two pathways through which HDCA activated PPARα. First, HDCA increased the number of invariant natural killer T (iNKT) cells, a type of immune cell, in the liver. These cells produced more interferon-γ (IFN-γ), a signaling molecule that activated PPARα in liver cells. PPARα then switched on the genes that help liver cells break down fatty acids.

As another pathway, HDCA also increased the levels of glucagon-like peptide-1 (GLP-1), a gut hormone that helps regulate metabolism. The researchers found that GLP-1 signaling was necessary for HDCA to reduce liver fat. When they tested mice that lacked the GLP-1 receptor, HDCA could no longer prevent fat from accumulating in the liver.

To further examine the role of GLP-1 and its relationship with iNKT cells and PPARα, the researchers injected liraglutide, a drug that activates the GLP-1 receptor and is used to treat type 2 diabetes, into normal mice and mice lacking iNKT cells, PPARα, or the GLP-1 receptor. Liraglutide reduced liver fat in both normal mice and mice lacking iNKT cells, but not in mice lacking PPARα. These findings indicated that GLP-1 reduces liver fat through PPARα and does not require iNKT cells.

Together, the researchers showed that HDCA may combat MASLD through two distinct pathways: an immune pathway involving iNKT cells and IFN-γ, and a metabolic pathway involving GLP-1. Both pathways ultimately activate PPARα, which helps the liver increase fatty-acid breakdown and reduce fat accumulation.

“Both HDCA and the GLP-1 receptor agonist liraglutide exhibited potent anti-steatotic effects in mice in a PPARα-dependent manner,” says Prof. Miki, highlighting PPARα as a potential target for developing strategies to combat MASLD.

Overall, these findings emphasize the potential of HDCA as an effective multi-target therapeutic strategy for the treatment of hepatic steatosis.

To see more news from Chiba University, click here.

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Reference:

Title of original paper: Hyodeoxycholic acid suppresses hepatic steatosis in a PPARα-dependent manner via distinct GLP-1- and iNKT cell-mediated pathways

Journal: Cell Reports

DOI: 10.1016/j.celrep.2026.117822

Authors: Eunyoung Lee^1,2,6,7, Ryo Hatano¹, Mariko Takami³, Masanori Fujimoto⁴, Hayato Yoshikawa¹, Yukihiro Endo⁵, Ryo Koyama-Nasu⁵, Atsushi Onodera^6,7, Jing Li^2,8, Sergio Rodriguez-Cuenca², Sonia Rodriguez-Fdez^2,9, Ioannis Kamzolas^2,10, Yu-Hung Lin^2,11, Guillaume Bidault², Tomoe Noda¹, Hitoshi Shimano¹², Motoko Y. Kimura⁵, Shinichiro Motohashi³, Tomoaki Tanaka^4,7, Antonio Vidal-Puig^2,7,9,13, and Takashi Miki^1,7

Affiliations: ¹Department of Medical Physiology, Graduate School of Medicine, Chiba University, Japan

²Metabolic Research Laboratories, MRC Institute of Metabolic Science, Addenbrooke’s Hospital, University of Cambridge, UK

³Department of Medical Immunology, Graduate School of Medicine, Chiba University, Japan

⁴Department of Molecular Diagnosis, Graduate School of Medicine, Chiba University, Japan

⁵Department of Experimental Immunology, Graduate School of Medicine, Chiba University, Japan

⁶Institute for Advanced Academic Research, Chiba University, Japan

⁷Research Institute of Disaster Medicine (RIDM), Chiba University, Japan

⁸School of Life Sciences, Nanjing University, China

⁹Victor Phillip Dahdaleh Heart & Lung Research Institute, UK

¹⁰European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, UK

¹¹Department of Surgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Taiwan

¹²Department of Endocrinology and Metabolism, Institute of Medicine, University of Tsukuba, Japan

¹³Centro de Investigacion Principe Felipe, Spain

About Professor Takashi Miki from Chiba University, Japan
Dr. Takashi Miki is a Professor, Dean, and Director at Chiba University’s Graduate School of Medicine. His research focuses on the regulation of sugar and energy metabolism, with particular interest in inter-organ networks and intracellular signaling pathways. He investigates new approaches for treating metabolic disorders, including diabetes, obesity, and non-alcoholic fatty liver disease. He also contributes to disaster medicine research, working toward stronger health protection and resilience during emergencies and disasters.

Funding:
This work was supported by Grant-in-Aid from the Ministry of Education, Science, Sports and Culture of Japan (19K06757 to Eunyoung Lee, 20K08583 to Ryo Hatano, and 22H02800, 25K02439 to Takashi Miki.) and by JST grant number JPMJPF2301. It was also funded by a Wellcome Trust strategic award (100574/Z/12/Z), MRC MDU (MC_UU_12012/2), H2020 EPoS (Elucidating Pathways of Steatohepatitis grant agreement 634413), the British Heart Foundation (RG/18/7/33636), and LITMUS (Liver Investigation: Testing Marker Utility in Steatohepatitis) project, which has received funding from the Innovative Medicines Initiative (IMI2) Program of the European Union under grant agreement 777377 (S.R.-C., G.B., S.R.-F., I.K., and A.V.-P.). Furthermore, this work was also supported by a National Institute for Health Research Biomedical Research Centre (NIHR BRC) Gastrointestinal Diseases pump-priming grant.