Critical in vivo roles of histamine and histamine receptor signaling in animal models of metabolic syndrome

Abstract

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.

Peroxiredoxin 4 (PRDX4): Its critical in vivo roles in animal models of metabolic syndrome ranging from atherosclerosis to nonalcoholic fatty liver disease

“…In contrast to lipid metabolism in humans, the lipoprotein profile in mice is high‐density lipoprotein (HDL)‐dominant; as such, WT mice are essentially resistant to high‐cholesterol diet (HcD)‐induced atheromatous plaque formation . Thus, to achieve hypercholesterolemia‐induced atheromatous formation, we generated Tg and apolipoprotein E ( apoE )‐knockout ( apoE −/ −) mice ( hPRDX4 +/+ /apoE −/− ) by crossing apoE ‐KO mice .…”

Peroxiredoxin 4 (PRDX4): Its Critical <em>In Vivo</em> Roles in Animal Models of Metabolic Syndrome Using Our Unique PRDX4 Transgenic Mice

“…We also provide the first evidence that the small intestine as well as the liver are spared by process may also significantly reduce the intestinal fat absorption capacity at the mucosal surface, where nutrient absorption mainly takes place [39]. Taken function protecting against enterobacterial invasion [78][79][80].…”

“…Taken together, these previous findings and our in vivo data indicate that metabolic syndrome is an extremely complex disease orchestrated by multiple molecular and histopathologic factors, including not only oxidative stress but also elevated levels of inflammatory cytokines and apoptotic activity and the translocation of either intestinal bacteria or microbial cell components [8][9][10][11][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40]. All researchers should be aware of the fact that lipid/bile acid (BA)/glucose metabolism with both local (each tissue) and whole-body functions plays a central, key role in the etiology of metabolic syndrome.…”

“…Since BA/lipid metabolism strongly correlates with the pathogenesis of metabolic syndrome, including atherosclerosis and/or NAFLD, the establishment of BDL mice model is critical for clarifying its biochemical/molecular mechanisms in human cholestatic liver injury diseases as well as potentially atherosclerosis and NAFLD. Indeed, BAs are known to be synthesized in hepatocytes from lipids and cholesterol and to contain variable types of cholic acid (CA), and each BA demonstrates a specific affinity to BA receptors and functions as a signaling molecule with distinctive effects inducing oxidative stress, cytotoxicity, and/or apoptosis [38,39,82]. It has been suggested that metabolic syndrome may have a close correlation with higher levels of secondary BAs, such as deoxy-CA, resulting from major changes in the intestinal microbial flora, at least in part [39,83].…”

“…Indeed, BAs are known to be synthesized in hepatocytes from lipids and cholesterol and to contain variable types of cholic acid (CA), and each BA demonstrates a specific affinity to BA receptors and functions as a signaling molecule with distinctive effects inducing oxidative stress, cytotoxicity, and/or apoptosis [38,39,82]. It has been suggested that metabolic syndrome may have a close correlation with higher levels of secondary BAs, such as deoxy-CA, resulting from major changes in the intestinal microbial flora, at least in part [39,83]. Our laboratory has therefore been focusing on the early-phase BA metabolism and antioxidative response mediated intra-and extra-cellularly by PRDX4 in cholestatic Tg mice, developing a detailed BA profile and examining the function of the liver and small intestine.…”