Insulin regulates liver metabolism in vivo in the absence of hepatic Akt and Foxo1

Lu, Mingjian; Wan, Min; Leavens, Karla F.; Chu, Qingwei; Monks, Bobby R.; Fernandez, Sully; Ahima, Rexford S.; Ueki, Kohjiro; Kahn, C. Ronald; Birnbaum, Morris J.

doi:10.1038/nm.2686

Cited by 330 publications

(372 citation statements)

References 63 publications

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“…One branch leads through mTORC1 and activates lipid synthesis through an increase in SREBP-1c; the other branch bypasses mTORC1 and leads to a reduction in gluconeogenesis mediated by a reduction in the activity of Foxo1 (18). Here we show that the branch leading to increased SREBP-1c itself bifurcates distal to mTORC1.…”

Section: Discussionmentioning

confidence: 60%

Insulin stimulation of SREBP-1c processing in transgenic rat hepatocytes requires p70 S6-kinase

Owen¹,

Zhang²,

Bae³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

241

217

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Insulin activates sterol regulatory element-binding protein-1c in liver, thereby increasing fatty acid and triglyceride synthesis. We created a line of transgenic rats that produce epitopetagged human SREBP-1c in liver under control of the constitutive apolipoprotein E promoter/enhancer. This system allows us to dissect the pathway by which insulin stimulates SREBP-1c processing without interference by the insulin-mediated increase in SREBP-1c mRNA. Rats are used because freshly isolated rat hepatocytes respond much more robustly to insulin than do mouse hepatocytes. The data reveal that insulin-mediated stimulation of SREBP-1c processing requires the mechanistic target of rapamycin complex 1 (mTORC1), which also is required for insulin-mediated SREBP-1c mRNA induction. However, in contrast to mRNA induction, insulin stimulation of SREBP-1c processing is blocked by an inhibitor of p70 S6-kinase. The data indicate that the pathways for insulin enhancement of SREBP-1c mRNA and proteolytic processing diverge after mTORC1. Stimulation of processing requires the mTORC1 target p70 S6-kinase, whereas induction of mRNA bypasses this enzyme. Insulin stimulation of both processes is blocked by glucagon. The transgenic rat system will be useful in further defining the molecular mechanism for insulin stimulation of lipid synthesis in liver in normal and diabetic states. T he liver plays a unique role in lipid metabolism because it is the only organ that synthesizes fatty acids (FAs) and triglycerides (TGs) for export to other tissues. These synthetic processes are controlled reciprocally by insulin and glucagon, which are secreted by the pancreas and delivered directly to the liver via the portal vein. Precise control is important because excess FA synthesis leads to elevated FAs in muscle, thereby contributing to the peripheral insulin resistance and lipotoxicity seen in type 2 diabetes. Excess FA synthesis also causes fatty liver, which sometimes leads to cirrhosis and liver failure (1, 2).Insulin stimulates FA synthesis in liver by increasing the mRNA and the processed nuclear form of sterol regulatory elementbinding protein-1c (SREBP-1c), a transcription factor that activates all the genes needed to produce FAs and TGs in liver (3). Of the three SREBP isoforms, SREBP-1c is the one whose expression is highest in liver, and it is the only one that is controlled primarily by insulin. For this reason, definitive studies of insulin-mediated activation of SREBP-1c must be performed with liver cells.Studies of insulin action on liver cells are difficult because none of the established hepatocyte cell lines responds to insulin with the robustness observed in the livers of living animals. Moreover, freshly isolated hepatocytes lose their insulin responsiveness within 48-72 h after isolation. Therefore, studies must be performed in living animals or with freshly isolated hepatocytes that are less than 72 h old. Even more perplexing are species differences. Although mouse and rat livers manifest robust elevations in SREBP-1c mRNA...

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Section: Discussionmentioning

confidence: 60%

Insulin stimulation of SREBP-1c processing in transgenic rat hepatocytes requires p70 S6-kinase

Owen¹,

Zhang²,

Bae³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

241

217

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“…Requirement of Akt for Albumin Production-Akt, also known as protein kinase B, is a ubiquitous serine/threonine protein kinase that mediates many of the metabolic effects of insulin (34,35). We investigated whether Akt is required for the regulation of albumin production downstream of IR.…”

Section: Resultsmentioning

confidence: 99%

Insulin Is Required to Maintain Albumin Expression by Inhibiting Forkhead Box O1 Protein

Chen

Monks

et al. 2016

Journal of Biological Chemistry

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Diabetes is accompanied by dysregulation of glucose, lipid, and protein metabolism. In recent years, much effort has been spent on understanding how insulin regulates glucose and lipid metabolism, whereas the effect of insulin on protein metabolism has received less attention. In diabetes, hepatic production of serum albumin decreases, and it has been long established that insulin positively controls albumin gene expression. In this study, we used a genetic approach in mice to identify the mechanism by which insulin regulates albumin gene transcription. Albumin expression was decreased significantly in livers with insulin signaling disrupted by ablation of the insulin receptor or Akt. Concomitant deletion of Forkhead Box O1 (Foxo1) in these livers rescued the decreased albumin secretion. Furthermore, activation of Foxo1 in the liver is sufficient to suppress albumin expression. These results suggest that Foxo1 acts as a repressor of albumin expression.

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“…On the other hand, when Akt signaling is completely abrogated, such as in high-dose Akti-1/2 (i.e. above 2.5 M) and S961 experiments, or in published knock-out models, all pathways reliant on activation by Akt are shut off (31,34,37).…”

Section: Discussionmentioning

confidence: 99%

Pathogenesis of Selective Insulin Resistance in Isolated Hepatocytes

Cook

Langlet

Kido

et al. 2015

Journal of Biological Chemistry

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Background:The liver produces both excessive glucose and lipids in type 2 diabetes. Results: Glucose production is more vulnerable to insulin receptor (InsR) impairment ex vivo than is lipogenesis. Conclusion: Selective insulin resistance arises due to inherent, cell-autonomous differences in the insulin responsiveness of glucose versus lipid metabolism. Significance: InsR itself may represent a locus of treatment of diabetes.

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Insulin regulates liver metabolism in vivo in the absence of hepatic Akt and Foxo1

Cited by 330 publications

References 63 publications

Insulin stimulation of SREBP-1c processing in transgenic rat hepatocytes requires p70 S6-kinase

Insulin stimulation of SREBP-1c processing in transgenic rat hepatocytes requires p70 S6-kinase

Insulin Is Required to Maintain Albumin Expression by Inhibiting Forkhead Box O1 Protein

Pathogenesis of Selective Insulin Resistance in Isolated Hepatocytes

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