Histamine, a classic low-molecular-weight
amine, is synthesized from
L-histidine by
histidine decarboxylase (HDC), and
histamine-specific receptors (HRs) are essential for its actions. Our serial in vivo studies have uniquely reported that expression of
histamine/HRs is variably identified in atherosclerotic lesions, and that HDC-gene knockout mice without
histamine/HRs signaling show a marked reduction of atherosclerotic progression. These data have convinced us that
histamine plays a pivotal role in the pathogenesis of
atherosclerosis. Among four subclasses of HRs, the expression profile of the main
receptors (H1/2R) has been shown to be switched from H2R to H1R during monocyte to macrophage differentiation, and H1R is also predominant in smooth muscle and endothelial cells of
atheromatous plaque. Using various animal models of H1/2R-gene knockout mice, H1R and H2R were found to reciprocally but critically regulate not only
hypercholesterolemia-induced
atherosclerosis and injury-induced
arteriosclerosis, but also
hyperlipidemia-induced
nonalcoholic fatty liver disease (
NAFLD).
Metabolic syndrome manifests
obesity,
dyslipidemia,
insulin resistance,
atherosclerosis, and/or
NAFLD, i.e. the dysregulation of
lipid/
bile acid/
glucose metabolism. Therefore, although its etiology is complicated and multifactorial,
histamine/HRs signaling has a close relationship with the development of
metabolic syndrome. We herein review diverse, key in vivo roles of
histamine/HR signaling in the pathogenesis of
metabolic syndrome.