Bile Acid HDCA Reduces Liver Fat via PPARα, With Takashi Miki, MD, PhD

Researchers at Chiba University have identified a bile acid capable of reducing liver fat in mice without weight loss, a finding with implications for metabolic dysfunction-associated steatotic liver disease (MASLD).¹ In the study, published in Cell Reports, hyodeoxycholic acid (HDCA) at a 0.25% dose reduced blood glucose, lowered hepatic triglyceride content, and improved liver function in high-fat diet-fed mice while body weight stayed unchanged.¹,² The authors concluded the reduction in liver fat was not a byproduct of weight loss.²

The project, a collaboration with the University of Cambridge, began when adipose tissue transplantation raised circulating HDCA levels in the team’s diabetic mouse model.² “This intriguing finding prompted us to investigate HDCA’s potential metabolic effects,” Takashi Miki, MD, PhD, dean of the Graduate School of Medicine at Chiba University and the study’s lead investigator, said in a statement.² The investigators traced HDCA’s effect to peroxisome proliferator-activated receptor α (PPARα), a nuclear receptor which switches on genes for fatty acid breakdown in the liver, as HDCA no longer worked in mice lacking it.²

HDCA reached PPARα through 2 separate routes.² In the first, HDCA increased invariant natural killer T (iNKT) cells, an immune cell population in the liver, which released interferon-γ to activate PPARα.² In the second, HDCA raised levels of the gut hormone glucagon-like peptide-1 (GLP-1), and its effect disappeared in mice lacking the GLP-1 receptor.²

In a written interview with HCPLive, Miki described how the project took shape, how the immune and hormonal pathways converge on PPARα, and what HDCA’s effect without weight loss suggests about how it works.

Q&A: HDCA, iNKT Cells, and GLP-1 in Hepatic Steatosis

HCPLive: What prompted your team to study hyodeoxycholic acid in hepatic steatosis, and what were the key findings?

Takashi Miki, MD, PhD: We previously reported that transplantation of wild-type adipose tissue into a mouse model of high-fat diet-induced diabetes (InsrP1195L/+ mice fed a high-fat diet) ameliorated hyperglycemia (Lee et al., Scientific Reports, 2015). Since these mice were found to exhibit an altered bile acid composition, we hypothesized that adipose tissue transplantation might lower blood glucose levels, at least in part, by modifying the bile acid profile. Indeed, we found that transplantation increased the circulating levels of a specific group of bile acids, namely, hyodeoxycholic acid (HDCA) and other hyocholic acid (HCA)-related species.

We subsequently investigated whether HDCA supplementation could reproduce the beneficial effects of adipose tissue transplantation. We found that HDCA not only ameliorated hyperglycemia but also markedly attenuated high-fat diet-induced hepatic steatosis in these mice. These findings prompted us to further investigate the potential of HDCA to prevent diet-induced hepatic steatosis in wild-type mice.

HCPLive: HDCA works through an iNKT cell/IFN-γ pathway and a GLP-1 pathway, both converging on PPARα. How do these work, and why does the convergence matter?

Takashi Miki, MD, PhD: At the outset of our study, we hypothesized that HDCA increases GLP-1 levels, which in turn activates iNKT cells to suppress hepatic steatosis. However, we found that a GLP-1 receptor agonist could suppress hepatic steatosis even in iNKT cell-deficient mice. This finding indicated that the GLP-1-mediated pathway can operate independently of iNKT cells, suggesting that HDCA exerts its anti-steatotic effects through multiple distinct pathways.

Importantly, we found that PPARα is essential for the amelioration of hepatic steatosis through these pathways. This convergence on PPARα suggests that activation of PPARα signaling may represent a key therapeutic mechanism for reducing hepatic steatosis and could provide a basis for developing novel therapeutic strategies.

HCPLive: HDCA reduced liver fat without affecting body weight. Why is that notable, given many current approaches to MASLD rely on weight loss?

Takashi Miki, MD, PhD: We found that HDCA reduces hepatic steatosis independently of body weight reduction. This is an important finding because weight loss itself is known to have beneficial effects on hepatic steatosis. Demonstrating that HDCA can reduce liver fat without affecting body weight therefore suggests that its anti-steatotic effect is not merely a secondary consequence of weight loss, but rather reflects a more direct metabolic action on the liver. This finding provides an important clue to understanding the mechanisms through which HDCA suppresses hepatic triglyceride accumulation.

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

References

1. 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

2. 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