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.