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.