Chromatin Correction with Secondary Bile Acid is Involved in the Amelioration of Developmentally-Programmed Hepatic Steatosis

We recently reported that a treatment with tauroursodeoxycholic acid (TUDCA), a secondary bile acid, improved developmentally-deteriorated hepatic steatosis in an undernourishment (UN, 40% caloric restriction) in utero mouse model after a postnatal high-fat diet (HFD). We performed a microarray analysis and focused on two genes (Cidea and Cidec) because they are enhancers of lipid droplet (LD) sizes in hepatocytes and showed the greatest increases in expression by UN that were completely recovered by TUDCA, concomitant with parallel changes in LD sizes. TUDCA remodeled developmentally-induced histone modifications (di-methylation of H3K4, H3K27, or H3K36), but not DNA methylation, around the Cidea and Cidec genes, leading to a heterochromatin structure, which contributed to the markedly down-regulated expression of their genes as well as hepatic fat deposition in UN pups only, even those under HFD. These results provide an insight into the future of precision medicine for developmentally-programmed hepatic steatosis by targeting chromatin reconstitution. Funding Statement: This work was supported in part by MEXT KAKENHI (Grant-in-Aid for Scientific Research) Grant Number JP16K15703. Declaration of Interests: None of the authors have anything to disclose. Ethics Approval Statement: All animal procedures were approved by the Institutional Animal Research Committee of Hamamatsu University School of Medicine (H20-014) and conducted in accordance with the ARRIVE guidelines and the standards of humane animal care by the criteria outlined in the “Guide for the Care and Use of Laboratory Animals”.