FFA-Fetuin-A regulates DPP-IV expression in pancreatic beta cells through TLR4-NFkB pathway

Biochem Biophys Res Commun. 2023 Mar 5:647:55-61. doi: 10.1016/j.bbrc.2023.01.070. Epub 2023 Jan 23.


Dipeptidyl peptidase 4 (DPP-IV) is a ubiquitous proteolytic enzyme that cleaves incretin hormones, such as glucagon-like peptide 1 (GLP1) and gastric inhibitory protein (GIP), leading to reduced glucose stimulated insulin secretion from the pancreatic beta cells. The functionally active enzyme is present in a membrane bound form in several cell types as well as in a soluble form in the circulation. The present report deals with DPP-IV expression and its regulation in the pancreatic beta cells in presence of free fatty acids (FFAs) and Fetuin-A, a circulatory glycoprotein associated with insulin resistance in humans and animals. FFA and Fetuin-A individually or in combination trigger DPP-IV expression in MIN6 cells. Islets isolated from high fat diet fed (HFD) mice (16 weeks) showed higher levels of DPP-IV expression than standard diet (SD) fed mice. Fetuin-A increased DPP-IV expression in HFD mice (4 weeks). Inhibition of TLR4 or NFkB prevented palmitate-Fetuin-A mediated DPP-IV expression in MIN6. It has been seen that Fetuin-A alone also could trigger DPP-IV expression in MIN6 cells via NFkB. Additionally, palmitate treatment exhibited reduced level of soluble DPP-IV in the media of MIN6 culture, which corroborated with the expression pattern of its protease, KLK5 that cleaves and releases the membrane bound DPP-IV into the secretion. Our results demonstrate that FFA-Fetuin-A upregulates DPP-IV expression in the pancreatic beta cells through the TLR4-NFkB pathway.

Keywords: DPP-IV; Fetuin-A; NFkB; Palmitate; Pancreatic beta cell; TLR4.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Dipeptidyl Peptidase 4 / metabolism
  • Dipeptidyl-Peptidase IV Inhibitors*
  • Fatty Acids, Nonesterified / metabolism
  • Humans
  • Insulin / metabolism
  • Insulin-Secreting Cells* / metabolism
  • Mice
  • Palmitates / metabolism
  • Toll-Like Receptor 4 / metabolism
  • alpha-2-HS-Glycoprotein / metabolism


  • alpha-2-HS-Glycoprotein
  • Toll-Like Receptor 4
  • Dipeptidyl Peptidase 4
  • Fatty Acids, Nonesterified
  • Palmitates
  • Insulin
  • Dipeptidyl-Peptidase IV Inhibitors
  • TLR4 protein, human
  • Tlr4 protein, mouse