Oral Presentation Australian Diabetes Society and the Australian Diabetes Educators Association Annual Scientific Meeting 2017

Fibroblast activation protein is important for glucose homeostasis, insulin resistance, lipid metabolism and liver steatosis (#176)

Sumaiya Chowdhury 1 , Hui (Emma) Zhang 1 , Sunmi Song 1 , Margaret G Gall 1 , Xin M Wang 1 , Denise MT Yu 1 , Kathryn A Evans 1 , Lisa Lo 2 3 , Yolanda Liu 1 , Mohammed Eslam 4 , Angelina Lay 1 , Nigel Turner 5 , Gregory Cooney 3 , Leon A Adams 6 , Kathryn H Willams 3 , Jacob George 4 , Geoffrey W McCaughan 1 7 , Susan V McLennan 2 3 , Stephen M Twigg 2 3 , Mark D Gorrell 1 3
  1. Centenary Institute and Sydney Medical School, The University of Sydney, NSW, Australia
  2. Department of Endocrinology, Royal Prince Alfred Hospital, NSW, Australia
  3. The Charles Perkins Centre and Sydney Medical School, The University of Sydney, NSW, Australia
  4. Storr Liver Unit, Westmead Hospital, NSW; Sydney Medical School, University of Sydney, NSW, Australia
  5. Faculty of Medicine, University of New South Wales, Kensington, NSW, Australia
  6. School of Medicine and Pharmacology, The University of Western Australia, Perth, WA, Australia
  7. A.W. Morrow Gastroenterology and Liver Centre, Royal Prince Alfred Hospital, NSW, Australia

Background/ Aim: Fibroblast activation protein (FAP) is a post-proline peptidase that has both endopeptidase and dipeptidyl peptidase (DPP) activities. Its closest relative DPP4, is the target of a successful class of antihyperglycemic drug, the gliptins. Here we studied the role of FAP in a diet induced obesity (DIO) mouse model and in human NASH.

Methods: Wild type (WT), FAP gene knockout (gko; lacks FAP) and FAP gene knockin (gki; lacks FAP enzyme activity) mice were in a DIO model. Glucose tolerance, insulin sensitivity, serum insulin, serum cholesterol, liver function test, liver lipids, respiratory exchange ratio (RER) (vCO2/vO2) were measured. Circulating FAP (cFAP) was measured in serum from NASH patients (n=146).

 

Results: FAP gko and FAP gki mice had improved glucose tolerance and insulin sensitivity from 8 weeks of DIO. FAP gko mice were protected from DIO-induced hyperinsulinemia and insulin resistance. FAP gko mice were resistant from DIO-induced fatty liver, as seen by less micro and macro-vesicular inclusions in the liver, less hepatocyte ballooning, less liver lipid, less serum alanine transaminase (ALT) and circulating cholesterol. FAP gko mice had lower RER and increased intrahepatic non-esterified free fatty acids, indicative of increased lipolysis and b-oxidation. Lipogenic genes PPARg and GCK and genes of hepatic triglyceride and fatty acid uptake, APOC3 and CD36, were downregulated in FAP gko livers. Gluconeogenic gene, Foxo1 was upregulated in fasting but not in fed FAP gko livers. Analyses of FAP gki are ongoing. In human NASH, cFAP activity correlated with circulating insulin (rs =0.246; p < 0.01) and HOMA-IR (rs =0.227; p <0.01).

 

Conclusion: These data show that FAP enzyme activity has important roles in glucose and lipid metabolism. FAP inhibition might become a novel treatment for obesity-induced glucose intolerance, insulin resistance, type 2 diabetes and fatty liver.

  1. KH Williams, AJ Vieira De Ribeiro, E Prakoso, A-S Veillard, NA Shackel, B Brooks, Y Bu, E Cavanagh, J Raleigh, SV McLennan, GW McCaughan, WW Bachovchin, FM Keane, A Zekry, SM Twigg, MD Gorrell 2015 Lower serum fibroblast activation protein shows promise in the exclusion of clinically significant liver fibrosis due to non-alcoholic fatty liver disease in diabetes and obesity. Diabetes Research and Clinical Practice 108: 466-472.