Lack of a‐CGRP Prevents High Fat Diet Induced Biliary Proliferation and Hepatic Steatosis

Nonalcoholic fatty liver disease (NAFLD) has become a prevalent problem in westernized societies where incidents of obesity lead to a reduction in blood flow and a deposition of fat into the liver increasing incidents of maladies ranging from minor nonclinical hepatic steatosis (NASH) to severe cirrhosis and cholangiocarcinoma (CCA). We have previously shown that cholangiocytes participate in a sub epithelial fibrotic process that is the hallmark of hepatobiliary injury. Employing a well‐established mouse model of mechanical liver injury through bile duct ligation (BDL), we have shown that cholangiocytes are regulated, in part, through sensory innervation, and manipulation of the innervation pathway through a‐calcitonin gene‐related peptide (a‐CGRP) signaling results in a reduction in cholangiocyte proliferation as well as liver fibrosis. Due to the fibrotic nature of fatty liver disease and our previous research demonstrating the interplay between cholangiocytes, neuropeptides, and sensory receptors, we AIM to evaluate the role a‐CGRP plays in the biliary progression from hepatic steatosis to the profibrotic phenotype found in the damaged biliary epithelium. METHODS Studies were performed in C57 (WT) and CGRP KO mice (4 wk of age). Mice were treated with Control and High Fat Diet (0.2% cholesterol, 45% fat calories, with 30% of the fat in the form of partially hydrogenated vegetable oil) with 45% fructose, 55% glucose (42g/L) drinking water for 20 wks. Fat deposition was visualized via Oil Red O staining. Ductular reaction (IBDM), CGRP accessory protein and collagen deposition was evaluated by IHC for CK‐19, RAMP1 and Sirius Red, respectively, in total liver sections. a‐CGRP was evaluated via protein expression in mouse total liver and mRNA in human tissue by IHC and q PCR. mRNA data for CLR, CALCRL, RAMP1, and CGRP was obtained via q PCR in pure cholangiocytes in WT CD and WT HFD. RESULTS There was a significant decrease in the fat deposition in the a‐CGRP KO HFD compared to the WT HFD. There was a significant decrease in IBDM and collagen deposition in CGRP KO HFD mice compared to WT HFD. Both mouse HFD and human steatotic livers showed significant increases in a‐CGRP when compared to their WT counterpart. Additionally, IHC demonstrated a significant increase in RAMP1 in the WT HFD when compared to CD. Cholangiocytes had significant increase in the expression of mRNA in the CGRP receptor (CLR), the receptor component (CGRPRC), its accessory, RAMP1, and the protein CGRP in HFD when compared to the WT CD. CONCLUSION a‐CGRP plays a substantial role in proliferation and hepatic fibrosis. Modulation of the a‐CGRP axis may represent a novel therapeutic approach for the management of NAFLD. Support or Funding Information NIH R01 DK76898 This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .