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Novel function of histamine signaling via histamine receptors in cholesterol and bile acid metabolism: Histamine H2 receptor protects against nonalcoholic fatty liver disease
Author(s) -
Yamada Sohsuke,
Guo Xin,
Wang KeYong,
Tanimoto Akihide,
Sasaguri Yasuyuki
Publication year - 2016
Publication title -
pathology international
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.73
H-Index - 74
eISSN - 1440-1827
pISSN - 1320-5463
DOI - 10.1111/pin.12423
Subject(s) - medicine , endocrinology , histamine , cholesterol , nonalcoholic fatty liver disease , bile acid , cholic acid , histamine receptor , liver x receptor , lipid metabolism , chemistry , biology , fatty liver , receptor , biochemistry , disease , nuclear receptor , gene , transcription factor , antagonist
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.