Hepatic Akt Activation Induces Marked Hypoglycemia, Hepatomegaly, and Hypertriglyceridemia With Sterol Regulatory Element Binding Protein Involvement

Abstract

Akt is critical in insulin-induced metabolism of glucose and lipids. To investigate functions induced by hepatic Akt activation, a constitutively active Akt, NH 2 -terminally myristoylation signal-attached Akt (myr-Akt), was overexpressed in the liver by injecting its adenovirus into mice. Hepatic myr-Akt overexpression resulted in a markedly hypoglycemic, hypoinsulinemic, and hypertriglyceridemic phenotype with fatty liver and hepatomegaly. To elucidate the sterol regulatory element binding protein (SREBP)-1c contribution to these phenotypic features, myr-Akt adenovirus was injected into SREBP-1 knockout mice. myr-Akt overexpression induced hypoglycemia and hepatomegaly with triglyceride accumulation in SREBP-1 knockout mice to a degree similar to that in normal mice, whereas myr-Akt-induced hypertriglyceridemia in knockout mice was milder than that in normal mice. The myr-Akt-induced changes in glucokinase, phosphofructokinase, glucose-6-phosphatase, and PEPCK expressions were not affected by knocking out SREBP-1, whereas stearoyl-CoA desaturase 1 induction was completely inhibited in knockout mice. Constitutively active SREBP-1-overexpressing mice had fatty livers without hepatomegaly, hypoglycemia, or hypertriglyceridemia. Hepatic acetylCoA carboxylase, fatty acid synthase, stearoyl-CoA desaturase 1, and glucose-6-phosphate dehydrogenase expressions were significantly increased by overexpressing SREBP-1, whereas glucokinase, phosphofructokinase, glucose-6-phosphatase, and PEPCK expressions were not or only slightly affected. Thus, SREBP-1 is not absolutely necessary for the hepatic Akt-mediated hypoglycemic effect. In contrast, myrAkt-induced hypertriglyceridemia and hepatic triglyceride accumulation are mediated by both Akt-induced SREBP-1 expression and a mechanism involving fatty acid synthesis independent of SREBP-1. Diabetes 52: 2905-2913, 2003 P hosphatidylinositol 3-kinase activation via insulin receptor substrate proteins and downstream Akt has been shown to play a critical role in insulininduced metabolic actions (1-3). In fat and muscle, the role of Akt has been widely recognized as mediation of insulin-stimulated glucose uptake (4 -6). Indeed, overexpression of constitutively active forms of Akt is sufficient to induce glucose transport in 3T3-L1 adipocytes and L6 muscle cells (7-9), whereas Akt2-deficient mice showed impaired glucose tolerance due to a decrease in insulin-induced glucose uptake in skeletal muscle and increased hepatic glucose production (10).On the other hand, in the liver, the rate of glucose utilization is determined by rate-limiting metabolic enzymes that catalyze glucose to generate triglyceride and glycogen by pathways known as glycolysis, lipogenesis, and glycogenesis. Moreover, the liver can produce glucose from lactate, pyruvate, and amino acids via gluconeogenesis and also from glycogen, via glycogenolysis, both of which are also rate limited by key metabolic enzymes at each step. Therefore, the rates of hepatic glucose input and output depend on rate-limiting metabolic ...

Normalization of Prandial Blood Glucose and Improvement of Glucose Tolerance by Liver-Specific Inhibition of SH2 Domain–Containing Inositol Phosphatase 2 (SHIP2) in Diabetic KKAy Mice

“…glycogen content and plasma triglycerides; this phenotype is again very similar to our data but much more pronounced because of the constitutive activity of Akt (24). A major new finding of our study is the marked reduction of prandial blood glucose levels.…”

Global metabolic effects of glycerol kinase overexpression in rat hepatoma cells

“…Further, a PathwayAssist analysis revealed that GK is closely linked to PPARα and SREBPs [2]. Recent studies have shown that G6PDH is a target gene for both PPARα, SREBP1c, and SREBP2 in liver [50,[57][58][59]. Together, these data indicate that it is likely that GK mediates the PPP through its network partners PPARα, SREBP1c, and SREBP2.…”

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.…”