Location: Arkansas Children's Nutrition Center
Title: Short term feeding of a high fat diet exerts an additive effect on hepatocellular damage and steatosis in liver-specific PTEN knockout mice Authors
|Shearn, Collin -|
|Mercer, Kelly -|
|Orlicky, David J -|
|Hennings, Leah -|
|Smathers-Mccullough, Rebecca -|
|Stiles, Bangyan -|
|Petersen, Dennis -|
Submitted to: PLoS One
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: April 8, 2014
Publication Date: May 12, 2014
Citation: Shearn, C.T., Mercer, K.E., Orlicky, D., Hennings, L., Smathers-Mccullough, R.L., Stiles, B.L., Petersen, D.R. 2014. Short term feeding of a high fat diet exerts an additive effect on hepatocellular damage and steatosis in liver-specific PTEN knockout mice. PLoS One. 9(5):e96553. Interpretive Summary: The purpose of this study was to examine the effects of a high fat diet in a model of pre-existing fatty liver. We found that when a diet high in unsaturated fatty acids is provided to mice that already are predisposed to fatty liver the effects are additive with respect to liver damage. Our data suggests that people with fatty liver should avoid diets rich in polyunsaturated fats.
Technical Abstract: Hepatospecific deletion of PTEN results in constitutive activation of Akt and increased lipogenesis. In mice, the addition of a high fat diet (HFD) downregulates lipogenesis. The aim of this study was to determine the effects of a HFD on hepatocellular damage induced by deletion of PTEN. Twelve-week-old male flox/flox hepatospecific PTEN mice (PTENf/f) or Alb-Cre controls were fed a HFD composed of 45% fat-derived calories (from corn oil) or a normal chow. Animals were then analyzed for hepatocellular damage, oxidative stress and expression of enzymes involved in fatty acid metabolism. In the Alb-Cre animals, the addition of a HFD resulted in a significant increase in liver triglycerides and altered REDOX capacity as evidenced by increased GPX activity, decreased GST activity and decreased hepatic concentrations of GSSG. In addition, SCD2, ACLY, and FASN were all downregulated by the addition of HFD. Furthermore, expression of PPARa and PPARa-dependent proteins Cyp4a and ACSL1 were upregulated. In the PTENf/f mice, HFD resulted in significant increase in ALT, serum triglycerides, and decreased REDOX capacity. Although expression of fatty acid synthetic enzymes was elevated in the chow-fed PTENf/f group, the addition of HFD resulted in SCD2, ACLY, and FASN downregulation. Compared to the Alb-Cre HFD group, expression of PGC1a, PPARa, and its downstream targets ACSL and Cyp4a were upregulated in PTENf/f mice. These data suggest that during conditions of constitutive Akt activation and increased steatosis, the addition of a HFD enhances hepatocellular damage due to increased CD36 expression and altered REDOX status. In addition, this work indicates HFD-induced hepatocellular damage occurs, in part, independently of Akt signaling.