Fibroblast activation protein in steatosis

Zhang HE1, Chowdhury S1, Hamson E1, Xiang M1, Lay A1 and Gorrell M1,2

  1. Centenary Institute.
  2. The University of Sydney.

Background & Aim: Better understanding of processes of glucose intolerance, insulin resistance and steatosis in diabetes and fatty liver is needed. Fibroblast activation protein (FAP) has a unique post-proline cleaving activity. Normal FAP expression is very low, but is greatly up-regulated in activated liver mesenchymal cells in human liver cirrhosis. Low level of FAP in human plasma strongly associates with lacking liver fibrosis. We aim to understand metabolic outcomes of specific deficiency of FAP activity in diet-induced obesity (DIO). Methods: Wildtype (WT) and FAPgki (gene-knockin; substituting the catalytic serine) mice were in a DIO model. Proteomics/degradomics was performed to identify novel natural substrates of FAP. Results: FAP activity in pancreas was greater in DIO-WT than chow-fed-WT mice. Compared to DIO-WT mice, DIO-FAPgki mice had less glucose intolerance, insulin resistance, insulin secretion, micro-vesicular steatosis, adiposity and circulating cholesterol. We previously found that FAP gene-knockout mice had increased intrahepatic non-esterified free fatty acids, indicative of increased lipolysis and β-oxidation. Concordantly, lipogenic genes (Pparγ, Gck, Acc, Fasn) and hepatic triglyceride and fatty acid uptake genes (Cd36, Apoc3, Ldlr) were downregulated in FAPgki livers. We identified natural substrates of FAP, such as LOXL-1, CSF-1, CCL-2, C1qT6 and FGF21, pointing to roles of FAP in ECM-cell interactions, metabolism and immunoregulation. The starvation hepatokine FGF21 was of particular interest. FGF21 was increased in FAP deficient DIO compared to WT DIO mice. Thus, these metabolic changes depend upon FAP activity and FAP action on FGF-21 is likely involved. Conclusion: This is the first study showing that specific genetic ablation of FAP activity, which mimics a specific potent inhibitor, is protective of DIO-driven glucose intolerance, insulin resistance and liver steatosis in mice.