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Increased basal level of Akt-dependent insulin signaling may be responsible for the development of insulin resistance.

ABSTRACT: A majority of subjects with insulin resistance and hyperinsulinemia can maintain their blood glucose levels normal for the whole life presumably through protein kinase B (Akt)-dependent insulin signaling. In this study, we found that the basal Akt phosphorylation level was increased in liver and gastrocnemius of mice under the high-fat diet (HFD). Levels of mitochondrial DNA and expression of some mitochondrion-associated genes were decreased by the HFD primarily in liver. Triglyceride content was increased in both liver and gastrocnemius by the HFD. Oxidative stress was induced by the HFD in both liver and gastrocnemius. Insulin sensitivity was decreased by the HFD. All of these changes were largely or completely reversed by treatment of animals with the phosphatidylinositol 3-kinase inhibitor LY-294002 during the time when animals usually do not eat. Consequently, the overall insulin sensitivity was increased by treatment with LY-294002. Together, our results indicate that increased basal Akt-dependent insulin signaling suppresses mitochondrial production, increases ectopic fat accumulation, induces oxidative stress, and desensitizes insulin signaling in subjects with insulin resistance and hyperinsulinemia.

SUBMITTER: Liu HY

PROVIDER: S-EPMC2763787 | biostudies-literature | 2009 Oct

REPOSITORIES: biostudies-literature

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Increased basal level of Akt-dependent insulin signaling may be responsible for the development of insulin resistance.

Liu Hui-Yu HY Hong Tao T Wen Ge-Bo GB Han Jianmin J Zuo Degen D Liu Zhenqi Z Cao Wenhong W

American journal of physiology. Endocrinology and metabolism 20090728 4

A majority of subjects with insulin resistance and hyperinsulinemia can maintain their blood glucose levels normal for the whole life presumably through protein kinase B (Akt)-dependent insulin signaling. In this study, we found that the basal Akt phosphorylation level was increased in liver and gastrocnemius of mice under the high-fat diet (HFD). Levels of mitochondrial DNA and expression of some mitochondrion-associated genes were decreased by the HFD primarily in liver. Triglyceride content w ...[more]

PMID: 19638508

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Project description:Background & aimsDe novo lipogenesis is believed to be involved in oncogenesis. We investigated the role of aberrant lipid biosynthesis in the pathogenesis of human hepatocellular carcinoma (HCC).MethodsWe evaluated expression of enzymes that regulate lipogenesis in human normal liver tissues and HCC and surrounding, nontumor, liver tissues from patients using real-time reverse transcription polymerase chain reaction, immunoblotting, immunohistochemistry, and biochemical assays. Effects of lipogenic enzymes on human HCC cell lines were evaluated using inhibitors and overexpression experiments. The lipogenic role of the proto-oncogene AKT was assessed in vitro and in vivo.ResultsIn human liver samples, de novo lipogenesis was progressively induced from nontumorous liver tissue toward the HCC. Extent of aberrant lipogenesis correlated with clinical aggressiveness, activation of the AKT-mammalian target of rapamycin signaling pathway, and suppression of adenosine monophosphate-activated protein kinases. In HCC cell lines, the AKT-mammalian target of rapamycin complex 1-ribosomal protein S6 pathway promoted lipogenesis via transcriptional and post-transcriptional mechanisms that included inhibition of fatty acid synthase ubiquitination by the USP2a de-ubiquitinase and disruption of the SREBP1 and SREBP2 degradation complexes. Suppression of the genes adenosine triphosphate citrate lyase, acetyl-CoA carboxylase, fatty acid synthase, stearoyl-CoA desaturase 1, or sterol regulatory element-binding protein 1, which are involved in lipogenesis, reduced proliferation, and survival of HCC cell lines and AKT-dependent cell proliferation. Overexpression of an activated form of AKT in livers of mice induced lipogenesis and tumor development.ConclusionsDe novo lipogenesis has pathogenic and prognostic significance for HCC. Inhibitors of lipogenic signaling, including those that inhibit the AKT pathway, might be useful as therapeutics for patients with liver cancer.

Dataset Information

Increased basal level of Akt-dependent insulin signaling may be responsible for the development of insulin resistance.

Publications

Increased basal level of Akt-dependent insulin signaling may be responsible for the development of insulin resistance.

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