{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,1]],"date-time":"2026-05-01T19:48:25Z","timestamp":1777664905965,"version":"3.51.4"},"reference-count":54,"publisher":"American Physiological Society","issue":"8","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["American Journal of Physiology-Gastrointestinal and Liver Physiology"],"published-print":{"date-parts":[[2014,10,15]]},"abstract":"<jats:p> Histidine is converted to histamine by histidine decarboxylase (HDC). We have shown that cholangiocytes 1) express HDC, 2) secrete histamine, and 3) proliferate after histamine treatment via ERK1\/2 signaling. In bile duct-ligated (BDL) rodents, there is enhanced biliary hyperplasia, HDC expression, and histamine secretion. This studied aimed to demonstrate that knockdown of HDC inhibits biliary proliferation via downregulation of PKA\/ERK1\/2 signaling. HDC<jats:sup>\u2212\/\u2212<\/jats:sup> mice and matching wild-type (WT) were subjected to sham or BDL. After 1 wk, serum, liver blocks, and cholangiocytes were collected. Immunohistochemistry was performed for 1) hematoxylin and eosin, 2) intrahepatic bile duct mass (IBDM) by cytokeratin-19, and 3) HDC biliary expression. We measured serum and cholangiocyte histamine levels by enzyme immunoassay. In total liver or cholangiocytes, we studied: 1) HDC and VEGF\/HIF-1\u03b1 expression and 2) PCNA and PKA\/ERK1\/2 protein expression. In vitro, cholangiocytes were stably transfected with shRNA-HDC plasmids (or control). After transfection we evaluated pPKA, pERK1\/2, and cholangiocyte proliferation by immunoblots and MTT assay. In BDL HDC<jats:sup>\u2212\/\u2212<\/jats:sup> mice, there was decreased IBDM, PCNA, VEGF, and HDC expression compared with BDL WT mice. Histamine levels were decreased in BDL HDC<jats:sup>\u2212\/\u2212<\/jats:sup>. BDL HDC<jats:sup>\u2212\/\u2212<\/jats:sup> livers were void of necrosis and inflammation compared with BDL WT. PKA\/ERK1\/2 protein expression (increased in WT BDL) was lower in BDL HDC<jats:sup>\u2212\/\u2212<\/jats:sup> cholangiocytes. In vitro, knockdown of HDC decreased proliferation and protein expression of PKA\/ERK1\/2 compared with control. In conclusion, loss of HDC decreases BDL-induced biliary mass and VEGF\/HIF-1\u03b1 expression via PKA\/ERK1\/2 signaling. Our data suggest that HDC is a key regulator of biliary proliferation. <\/jats:p>","DOI":"10.1152\/ajpgi.00188.2014","type":"journal-article","created":{"date-parts":[[2014,8,29]],"date-time":"2014-08-29T07:39:20Z","timestamp":1409297960000},"page":"G813-G823","source":"Crossref","is-referenced-by-count":21,"title":["Knockout of histidine decarboxylase decreases bile duct ligation-induced biliary hyperplasia via downregulation of the histidine decarboxylase\/VEGF axis through PKA-ERK1\/2 signaling"],"prefix":"10.1152","volume":"307","author":[{"given":"Allyson","family":"Graf","sequence":"first","affiliation":[{"name":"Scott &amp; White Healthcare, Temple, Texas;"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fanyin","family":"Meng","sequence":"additional","affiliation":[{"name":"Central Texas Veterans Health Care System, Temple, Texas;"},{"name":"Scott &amp; White Healthcare, Temple, Texas;"},{"name":"Texas A&amp;M Health Science Center, Temple, 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