Liver-specific deletion of negative regulator Pten results in fatty liver and insulin hypersensitivity

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

Steatohepatitis Induced by Intragastric Overfeeding in Mice *

“…PTEN antagonizes insulin signaling, and its deficiency leads to hepatic steatosis. 10,11 However, the PTEN protein levels were unchanged in the model (Fig. 5A).…”

“…The NAFLD/NASH models that are frequently employed are classified into three categories. The first group encompasses genetic models that produce obesity because of naturally occurring null mutations of genes such as leptin, 3 leptin receptor, 4,5 and agouti, 6 and those with deranged liver metabolism due to targeted ablation of peroxisome proliferator-activated receptor ␣ (PPAR␣), 7 acyl-CoA ox-idase, 8 MAT1A, 9 and phosphatase and tension homolog deleted on chromosome 10 (PTEN), 10,11 or targeted overexpression of sterol regulatory element binding protein 1 (SREBP-1) 12 and PPAR␥. 13 Although these genetic approaches are useful in assessing biological significance of each gene product in vivo, they do not reflect the natural etiological setting of the most common form of NAFLD/NASH in patients.…”

Oncogene dependent requirement of fatty acid synthase in hepatocellular carcinoma

“…In mice, overexpression of an activated form of AKT or liver-specific deletion of PTEN leads to increased FASN expression and its mediated lipogenesis, resulting in hepatic steatosis. [33][34][35] In human HCC cells, it has been found that AKT/mTOR/RPS6 cascades promotes lipogenesis via multiple mechanisms, including increased mRNA expression of FASN and other lipogenic pathway genes, decreased FASN degradation, and augmented stability of SREBP1/2. 33 Altogether, these lines of evidence indicate that the AKT/mTOR pathway is the major regulator of lipogenesis along hepatocarcinogenesis.…”

PTEN targeting: the search for novel insulin sensitisers provides new insight into obesity research

“…Studies on mice with PTEN ablation in liver [13,14], adipose [15] or skeletal muscle tissues [16] have investigated the effect of PTEN on whole-body glucose homeostasis. In general, this work has provided further support for a role for PTEN in insulin sensitivity and metabolic regulation (Table 1).…”

“…However, when subjected to a highfat diet, these animals showed protection against the development of hyperglycaemia and abnormalities in glucose tolerance. Cell proliferation in fat and muscle was not Liver-specific ablation Reduced fasting plasma insulin, enhanced glucose tolerance and insulin sensitivity [13,14] Fat-specific ablation Reduced fasting plasma insulin, enhanced glucose tolerance and insulin sensitivity [15] Muscle-specific ablation Protection from insulinresistance and diabetes when exposed to high-fat diet [16] Ubiquitous haploinsufficiency…”