Whether the stomach influences the progression of nonalcoholic steatohepatitis (NASH) remains largely unknown. Ghrelin, a 28‐amino acid gastric hormone, is critical for the regulation of energy metabolism and inflammation. We investigated whether ghrelin affects the progression of NASH. NASH was induced with lipopolysaccharide (LPS; 240 μg/kg/day) in male C57BL/6J mice with high‐fat diet (HFD). Ghrelin (11 nmol/kg/day) was administrated by a subcutaneous mini‐pump. Liver steatosis, inflammation, and fibrosis were assessed. Kupffer cells and hepatocytes isolated from wild type, GHSR1a−/−or PPARγ+/−mice were cocultured to determine the cellular and molecular mechanism by which ghrelin ameliorates NASH. A low concentration of LPS activates the Kupffer cells, leading to the development of NASH in mice fed HFD. Ghrelin blocked the progression of NASH induced by LPS via GHSR1a‐mediated attenuation of Kupffer cells M1 polarization. GHSR1a was detected in Kupffer cells isolated from wild‐type mice but not in GHSR1a deficient animals. Upon binding with ghrelin, internalization of GHSR1a occurred. Ghrelin reduced levels of tumor necrosis factor‐α and inducible nitricoxide synthase while increasing Arg1 in Kupffer cells treated with LPS. Ghrelin markedly attenuated the upregulation of lipid accumulation induced by the supernatant of Kupffer cells under both basal and LPS‐treated conditions. Deficiency of PPARγ significantly reduced the effect of LPS on the hepatic steatosis in mice and in cultured hepatocytes. Our studies indicate that the stomach may improve the development of NASH via ghrelin. Ghrelin may serve as a marker and therapeutic target for NASH.
While extensive investigations have been devoted to the study of genetic pathways related to fatty liver diseases, much less is known about epigenetic mechanisms underlying these disorders. DNA methylation is an epigenetic link between environmental factors (e.g., diets) and complex diseases (e.g., non‐alcoholic fatty liver disease). Here, it is aimed to study the role of DNA methylation in the regulation of hepatic lipid metabolism. A dynamic change in the DNA methylome in the liver of high‐fat diet (HFD)‐fed mice is discovered, including a marked increase in DNA methylation at the promoter of Beta‐klotho (
- Award ID(s):
- 2109051
- NSF-PAR ID:
- 10421051
- Publisher / Repository:
- Wiley Blackwell (John Wiley & Sons)
- Date Published:
- Journal Name:
- Advanced Science
- Volume:
- 10
- Issue:
- 20
- ISSN:
- 2198-3844
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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