Liver-specific deletion of negative regulator Pten results in fatty liver and insulin hypersensitivity [corrected] - PubMed (original) (raw)
Liver-specific deletion of negative regulator Pten results in fatty liver and insulin hypersensitivity [corrected]
Bangyan Stiles et al. Proc Natl Acad Sci U S A. 2004.
Erratum in
- Proc Natl Acad Sci U S A. 2004 Apr 6;101(14):5180
Abstract
In the liver, insulin controls both lipid and glucose metabolism through its cell surface receptor and intracellular mediators such as phosphatidylinositol 3-kinase and serine-threonine kinase AKT. The insulin signaling pathway is further modulated by protein tyrosine phosphatase or lipid phosphatase. Here, we investigated the function of phosphatase and tension homologue deleted on chromosome 10 (PTEN), a negative regulator of the phosphatidylinositol 3-kinase/AKT pathway, by targeted deletion of Pten in murine liver. Deletion of Pten in the liver resulted in increased fatty acid synthesis, accompanied by hepatomegaly and fatty liver phenotype. Interestingly, Pten liver-specific deletion causes enhanced liver insulin action with improved systemic glucose tolerance. Thus, deletion of Pten in the liver may provide a valuable model that permits the study of the metabolic actions of insulin signaling in the liver, and PTEN may be a promising target for therapeutic intervention for type 2 diabetes.
Figures
Fig. 1.
Liver-specific deletion of Pten. (A) Breeding strategy. (B) Liver-specific deletion of the Pten gene. PCR analysis of DNA from different tissues of _Pten_lox/lox;Alb-Cre+ mice. (C) Western analysis for PTEN (Top), _p_-AKT (Middle) and AKT (Bottom).
Fig. 2.
Pten deletion results in hepatomegaly and liver steatosis. (A) Hepatomegaly of mutant mice. Photo shows livers from mutant (Upper) and WT mouse (Lower); mutant mice have heavier livers (Upper Right; n = 6), increased liver to body weight ratio (Lower Left; n = 6), and increased TG storage (Lower Right; n = 6). *, P ≤ 0.05. (B) Histological analysis of liver sections from WT and mutant mice. (Top) Hematoxylin/eosin staining. (Middle) Periodic acid Schiff's staining (Bottom) Oil red O staining. (Bar, 50 μM.)
Fig. 3.
Pten deletion enhances FA synthesis and secretion by hepatocytes. (A) Uptake of long-chain FA by WT and mutant primary hepatocytes. (Left) Low-uptake group. (Right) High-uptake group. n = 3. (B) FA synthesis rate is calculated as newly synthesized portion of palmitate (Left, n = 6). Lipid secretion rate is measured as plasma TG levels at indicated time points after triton injection (Right, n = 3). (C) Lipid indexes of 1-month-old Pten WT and mutant mice: (Left Upper) body fat content of WT (n = 7) and mutant mice (n = 6). (Right Upper) Plasma NEFA levels in WT (n = 6) and mutant (n = 6) mice. (Left Lower) Plasma leptin levels in WT (n = 5) and mutant mice (n = 5). (Right Lower) Plasma TG levels in WT (n = 5) and mutant mice (n = 5). *, P ≤ 0.05.
Fig. 4.
Fasting plasma glucose and insulin levels. (A) Fasting plasma glucose levels in 1- (Left), 3- (Center), and 6-month-old (Right) mice. Open bars, WT (n = 9); filled bars, mutant (n = 11). (B) Fasting plasma insulin concentrations in 3- (Left) and 6-month-old (Right) mice. n = 6. *, P ≤ 0.05.
Fig. 5.
i.p. GTT. (A) One-month GTT with WT (n = 9) and mutant (n = 11) mice. (B) Three-month GTT with WT (n = 6) and mutant (n = 8) mice. (C) Six-month GTT with WT (n = 11) and mutant (n = 8) mice. *, P ≤ 0.05
Fig. 6.
Pten deletion results in inhibition of gluconeogenesis and activation of lipogenesis enzymes in the liver. (A) Western blot analysis of GSK-3β and FAS. Blots were probed with PTEN (first section), phospho-GSK-3β (second section), and FAS (fourth section). Actin and vinculin were used as loading controls. (B) Northern blot analysis of PEPCK and G6Pase gene expressions in mouse liver. Actin was used as loading control.
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