Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0015695 (fatty liver)
 13,941 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
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PMID:Critical in vivo roles of histamine and histamine receptor signaling in animal models of metabolic syndrome. 2786 77

Feeding a high-fat diet (HFD) coupled with sugar, mimicking a Western diet, causes fatty liver disease in mice. Histamine induces biliary proliferation and fibrosis and regulates leptin signaling. Wild-type (WT) and l-histidine decarboxylase (Hdc-/-) mice were fed a control diet or an HFD coupled with a high fructose corn syrup equivalent. Hematoxylin and eosin and Oil Red O staining were performed to determine steatosis. Biliary mass and cholangiocyte proliferation were evaluated by immunohistochemistry. Senescence and fibrosis were measured by quantitative PCR and immunohistochemistry. Hepatic stellate cell activation was detected by immunofluorescence. Histamine and leptin levels were measured by enzyme immunoassay. Leptin receptor (Ob-R) was evaluated by quantitative PCR. The HDC/histamine/histamine receptor axis, ductular reaction, and biliary senescence were evaluated in patients with nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, or end-stage liver disease. Hdc-/- HFD mice had increased steatosis compared with WT HFD mice. WT HFD mice had increased biliary mass, biliary proliferation, senescence, fibrosis, and hepatic stellate cell activation, which were reduced in Hdc-/- HFD mice. In Hdc-/- HFD mice, serum leptin levels increased, whereas biliary Ob-R expression decreased. Nonalcoholic steatohepatitis patients had increased HDC/histamine/histamine receptor signaling. Hdc-/- HFD mice are susceptible to obesity via dysregulated leptin/Ob-R signaling, whereas the lack of HDC protects from HFD-induced fibrosis and cholangiocyte damage. HDC/histamine/leptin signaling may be important in managing obesity-induced biliary damage.
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PMID:Knockout of l-Histidine Decarboxylase Prevents Cholangiocyte Damage and Hepatic Fibrosis in Mice Subjected to High-Fat Diet Feeding via Disrupted Histamine/Leptin Signaling. 2924 61