Q&A: HDCA, iNKT Cells, and GLP-1 in Hepatic SteatosisHCPLive: 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.
ReferencesLee 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.2026.117822Chiba 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