High Fat Diet-mediated p38α Activation in the Liver Contributes to the Onset of Insulin Resistance and Hepatic Steatosis
Year: 2020
Type: dissertation
Abstract: The mechanisms underlying the paradox of selective hepatic insulin resistance are not well understood. Mitogen-activated protein kinases play a pivotal role in the onset of hepatic metabolic dysregulation, however current data fails to establish a definitive role for p38. We generated a liver-specific p38α knockout (p38αKO) mouse model to investigate the role of p38α in regulating hepatic glucose and lipid metabolism following 1-week of high fat diet (HFD) feeding. Short-term HFD feeding increased hepatic p38 activation in mice. Moreover, p38αKO mice were protected from the development of HFD-induced hepatic and peripheral insulin resistance. HFD-mediated hepatic p38α activation increased plasma cytokines, suggesting a possible mechanism driving liver-periphery crosstalk in the development of peripheral insulin resistance. Lastly, HFD-induced activation of hepatic p38α promoted hepatic fat accumulation, potentially via enhanced hepatic PPAR-γ expression. These findings suggest that selective p38α inhibition may provide a new approach for treatment of insulin resistance and hepatic steatosis.
Source: TSpace (University of Toronto)
Author: Rivers, Sydney L
Language: English
Subfield: Hepatology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W3042461706