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. 2014 May 12;9(5):e96553.
doi: 10.1371/journal.pone.0096553. eCollection 2014.

Short term feeding of a high fat diet exerts an additive effect on hepatocellular damage and steatosis in liver-specific PTEN knockout mice

Colin T Shearn  1 , Kelly E Mercer  2 , David J Orlicky  3 , Leah Hennings  2 , Rebecca L Smathers-McCullough  4 , Bangyan L Stiles  5 , Martin J J Ronis  6 , Dennis R Petersen  1
Affiliations

Short term feeding of a high fat diet exerts an additive effect on hepatocellular damage and steatosis in liver-specific PTEN knockout mice

Colin T Shearn et al. PLoS One. .

Abstract

Background: 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.

Methods: 12 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.

Results: 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 PPARα and PPARα-dependent proteins Cyp4a and ACSL1 were upregulated. In the PTENf/f mice, HFD resulted in significant increased 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 PGC1α, PPARα and its downstream targets ACSL and Cyp4a were upregulated in PTENf/f mice.

Conclusions: 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.

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Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1
Figure 1. High fat diet results in increased lipid accumulation in PTENf/f mice.
Hematoxylin and eosin staining of tissue sections from chow/HFD-fed Alb-Cre and PTENf/f mice. (CV, central vein, PT, portal triad, BD, bile ducts). Original Magnification 400X.
Figure 2
Figure 2. HFD does not alter fibrosis in PTENf/f mice.
Picrosirius Red staining of tissue Hematoxylin and eosin staining of tissue sections from chow/HFD-fed Alb-Cre and PTENf/f mice. (A) White light. (B) Polarized light. (CV, central vein, PT, portal triad). Original Magnification 400X.
Figure 3
Figure 3. Effects of HFD on expression of GST's in Alb-Cre and PTENf/f.
Western blotting analysis of GSTA4, μ and μ using whole cell extracts isolated from chow/HFD-fed Alb-Cre and PTENf/f mice.
Figure 4
Figure 4. Effects of HFD on regulation of β-oxidation in Alb-Cre and PTENf/f.
Western blotting analysis of key enzymes involved in β-oxidation using whole cell extracts isolated from chow/HFD-fed Alb-Cre and PTENf/f mice.
Figure 5
Figure 5. Effects of HFD on regulation of hepatic lipogenesis in Alb-Cre and PTENf/f.
Western blotting analysis of de novo lipogenic enzymes using whole cell extracts isolated from chow/HFD-fed Alb-Cre and PTENf/f mice.
Figure 6
Figure 6. Effects of HFD on nuclear localization of metabolic transcription factors in Alb-Cre and PTENf/f mice.
Western blotting analysis of metabolic transcription factors using nuclear fractions isolated from chow/HFD-fed Alb-Cre and PTENf/f mice.
See this image and copyright information in PMC

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