Novel function of histamine signaling via histamine receptors in cholesterol and bile acid metabolism: Histamine H2 receptor protects against nonalcoholic fatty liver disease.
We have reported that the function of histamine and its receptors (HRs) has a close relationship with the development of nonalcoholic fatty liver disease (NAFLD). However, much less is known regarding its pathogenic and molecular mechanism(s), including the early stage of hepatic and intestinal function for lipid and bile acid (BA) metabolism. We used H1R and H2R knockout mice (H1/2R-KO) to clarify those pivotal roles in cholesterol/BA metabolism, in which H1/2R-KO mice were separately fed a short-term 1% cholesterol or cholic acid (CA) diet. [(3) H]Cholesterol absorption study revealed that significantly enhanced accumulation occurred in the jejunum, blood and liver, but not in the feces, of H2R-KO mice, compared to wild-type and H1R-KO mice. Furthermore, four weeks after the high-cholesterol diet, the H2R-KO jejunum but not liver exhibited increased expressions of cholesterol transporters, consistent with higher plasma lipoprotein levels. Five days after CA diet, the H2R-KO mice showed significantly higher expressions of ileal BA-reabsorption and hepatic BA-efflux factors, corresponding to higher serum but lower fecal BA levels. The following long-term CA diets resulted in severe injury to the H2R-KO liver. Histamine/H2R signaling might have a protective role in the initial phase during NAFLD progression, correlated with cholesterol and BA metabolism in the liver/intestine.
Department of Pathology, Field of Oncology, Kagoshima, University Graduate School of Medical and Dental Sciences, Kagoshima, Japan.|Department of Pathology and Cell Biology, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan.
Sohsuke
S
Yamada
Department of Pathology, Field of Oncology, Kagoshima, University Graduate School of Medical and Dental Sciences, Kagoshima, Japan.|Department of Pathology and Cell Biology, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan.|Laboratory of Pathology, Hebei Cancer Institute, the Fourth Hospital of Hebei, Medical University, Shijiazhuang, China.
Xin
X
Guo
Department of Pathology and Cell Biology, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan.|Shared-Use Research Center, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan.
Ke-Yong
KY
Wang
Department of Pathology, Field of Oncology, Kagoshima, University Graduate School of Medical and Dental Sciences, Kagoshima, Japan.
Akihide
A
Tanimoto
Laboratory of Pathology, Fukuoka Wajiro Hospital, Fukuoka, Japan.
Yasuyuki
Y
Sasaguri
D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism*; D002784:Cholesterol / Q000378:metabolism*; D006632:Histamine / Q000502:physiology*; D008099:Liver / Q000503:physiopathology; D051379:Mice; D065626:Non-alcoholic Fatty Liver Disease / Q000503:physiopathology*; D011970:Receptors, Histamine H2 / Q000378:metabolism*; D015398:Signal Transduction
D001647:Bile Acids and Salts; D011970:Receptors, Histamine H2; D006632:Histamine; D002784:Cholesterol
bile acid (BA) metabolism; cholesterol metabolism; cholic acid (CA) diet; high-cholesterol diet; histamine; histamine receptor (HR); nonalcoholic fatty liver disease (NAFLD)