Akt Stimulates Hepatic SREBP1c and Lipogenesis through Parallel mTORC1-Dependent and Independent Pathways

Yecies, Jessica L.; Zhang, Hui H.; Menon, Suchithra; Liu, Sihao; Lipovsky, Alex; Kwiatkowski, David J.; Hotamışlıgil, Gökhan S.; Lee, Chih‐Hao; Manning, Brendan D.

doi:10.1016/j.cmet.2011.07.004

Cited by 137 publications

(201 citation statements)

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“…Because of the fact that SREBP-1c regulation is not sensitive to insulin in isolated mouse hepatocytes (32, 54), we cannot examine whether compensatory hyperinsulinemia in insulin resistance drives DNL through the Akt 3 mTORC1 3 SREBP-1c pathway (1,32,33,55,56). We did find an increase in SREBP-1c mRNA and precursor protein levels following CHI treatment, as reported previously in rat hepatocytes (10,57).…”

Section: Discussionsupporting

confidence: 49%

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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Section: Discussionsupporting

confidence: 49%

Pathogenesis of Selective Insulin Resistance in Isolated Hepatocytes

Cook

Langlet

Kido

et al. 2015

Journal of Biological Chemistry

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“…In addition, SREBP-1a is a potent transcriptional activator for all known SREBP-target genes (7). The SREBP1 protein levels are often correlated with tumor size, histological grade and metastasis, and SREBP1 loss of function inhibits cell proliferation and induces apoptosis, cell migration and invasion in liver, ovarian and endometrial cancers (8)(9)(10)(11). Furthermore, genetic depletion or pharmacological inhibition of SREBP1 has been shown to suppress the epidermal growth factor receptor (EGFR)-induced glioblastoma (12).…”

mentioning

confidence: 99%

Pyruvate kinase M2 interacts with nuclear sterol regulatory element–binding protein 1a and thereby activates lipogenesis and cell proliferation in hepatocellular carcinoma

Zhao

Yang

et al. 2018

Journal of Biological Chemistry

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Dysregulation of lipid metabolism is common in cancer cells, but the underlying mechanisms are poorly understood. Sterol regulatory elementbinding proteins (SREBPs) stimulate lipid biosynthesis through transcriptional activation of lipogenic enzymes. However, SREBPs' roles and potential interacting partners in cancer cells are not fully defined. Using a biochemical approach, we found here that pyruvate kinase M2 (PKM2) physically interacts with the nuclear form of SREBP-1a (nBP1a), by binding to amino acids 43-56 in nBP1a. We also found that PKM2 activates SREBP target gene expression and lipid biosynthesis by stabilizing nBP1a proteins. Using a competitive peptide inhibitor to block the formation of the SREBP-1a/PKM2 complex, we observed that this blockade inhibited lipogenic gene expression. Of note, nBP1a phosphorylation at Thr-59 enhanced the binding to PKM2 and promoted cancer cell growth. Moreover, we show that PKM2 phosphorylates Thr-59 in vitro. Lastly, in human patients with hepatocellular carcinoma, nBP1a phosphorylation at Thr-59 was negatively correlated with clinical outcomes. Together, our results reveal that nBP1a/PKM2 interaction activates lipid metabolism genes in cancer cells and that Thr-59 phosphorylation of SREBP-1a plays an important role in cancer cell proliferation.Lipids are essential for cell proliferation. In fact, it has been estimated that more than 90% fatty acids in tumors cells are derived from de novo biosynthesis, while normal cells obtain lipids primarily from the circulation (1). In several types of cancer, including breast and prostate cancer, fatty acid synthase (Fasn) gene is up regulated (2), suggesting that fatty acid biosynthesis may play a role in cancer pathogenesis. Sterol regulatory element-binding proteins (SREBPs) are conserved transcription factors that can activate the transcription of genes encoding the key lipogenic enzymes, including Fasn (3,4). In mammalian cells, there are three SREBP isoforms (SREBP-1a, -1c and -2) encoded by two different genes, Srebf1 and Srebf2 (5). Two distinct promoters generate SREBP1a and SREBP-1c isoforms from the Srebf1 gene (5). Interestingly, Srebf1a is expressed at higher levels in cancer cells as compared to normal tissues, while Srebf1c is the predominant product of Srebf1 in normal tissues (6). In addition, SREBP-1a is a potent transcriptional activator for all known SREBP-target genes (7). The SREBP1 protein levels are often correlated with tumor size, histological grade and metastasis, and SREBP1 loss of function inhibits cell proliferation and induces apoptosis, cell migration and invasion in liver, ovarian and endometrial cancers (8)(9)(10)(11). Furthermore, genetic depletion or pharmacological inhibition of SREBP1 has been shown to suppress the epidermal growth factor receptor (EGFR)-induced glioblastoma (12). Blocking SREBP pathway prevents hepatocellular carcinoma (HCC) in mouse models (13). Thus, SREBP1 is required to support proliferation in some cancer cells.Previous studies have shown that pyruvate kinase isoform M...

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“…mTOR is a master switch of anabolism and catabolism. 9 Indeed, to avoid death and energy shortage, cells slow down their metabolism and inhibit anabolic reactions via the downregulation of the mTOR pathway. Other biological processes implicated in the resistance to apoptosis involve the phosphoinositide-3 kinase/Akt (PI3K/Akt) pathway.…”

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confidence: 99%