Effects of inhibiting PI3K-Akt-mTOR pathway on lipid metabolism homeostasis in goose primary hepatocytes

Liu, D. D.; Han, Chunchun; Wan, Huofu; He, Fang; Xu, Hengyong; Wei, Shuhong; Du, Xiaohui; Xu, Funeng

doi:10.1017/s1751731116000380

Cited by 56 publications

(41 citation statements)

References 33 publications

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“…In rat liver cells, the PI3K downstream effector mTORC1 was shown to be required for lipogenesis, yet was dispensable for gluconeogenesis (69). Similarly, Pan-PI3K or mTOR inhibition impaired lipogenesis and fatty acid oxidation in cultured hepatocytes, further substantiating the role of PI3K in maintaining proper lipid balance (70,12). Progression of PDAC can be caused by dysregulated cytokine status, which might be a major contributor to poor outcome in PDAC patients with NAFLD (35).…”

Section: Discussionmentioning

confidence: 92%

p110γ deficiency protects against pancreatic carcinogenesis yet predisposes to diet-induced hepatotoxicity

Torres

Mancinelli

Córdoba-Chacón

et al. 2019

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

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Pancreatic ductal adenocarcinoma (PDAC) is notorious for its poor survival and resistance to conventional therapies. PI3K signaling is implicated in both disease initiation and progression, and specific inhibitors of selected PI3K p110 isoforms for managing solid tumors are emerging. We demonstrate that increased activation of PI3K signals cooperates with oncogenic Kras to promote aggressive PDAC in vivo. The p110γ isoform is overexpressed in tumor tissue and promotes carcinogenesis via canonical AKT signaling. Its selective blockade sensitizes tumor cells to gemcitabine in vitro, and genetic ablation of p110γ protects against Kras-induced tumorigenesis. Diet/obesity was identified as a crucial means of p110 subunit up-regulation, and in the setting of a high-fat diet, p110γ ablation failed to protect against tumor development, showing increased activation of pAKT and hepatic damage. These observations suggest that a careful and judicious approach should be considered when targeting p110γ for therapy, particularly in obese patients.

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Section: Discussionmentioning

confidence: 92%

p110γ deficiency protects against pancreatic carcinogenesis yet predisposes to diet-induced hepatotoxicity

Torres

Mancinelli

Córdoba-Chacón

et al. 2019

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

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“…There was a decreased expression of proteins involved in the de novo fatty acid synthesis. Also, they found enhanced expression of key proteins of fatty acid oxidation [45].…”

Section: Discussionmentioning

confidence: 95%

“…It regulates gene expression by binding to specific PPAR-responsive elements (PPREs) on target gene promoters involved in fatty acid uptake, beta-oxidation and lipogenesis such as FATP, FABP, CPT-1, CPT-2,acyl-CoA dehydrogenases, LPL and SCD etc [50,51]. PI3K inhibitors have demonstrated an increase in the mRNA expression of PPARα and PPARγ [45]. In GDM, the placental PPAR α and γ protein expressions were reported to be lower when compared to CPW [53].…”

Section: Discussionmentioning

confidence: 99%

Placental Accumulation of Triacylglycerols in Gestational Diabetes Mellitus and Its Association with Altered Fetal Growth are Related to the Differential Expressions of Proteins of Lipid Metabolism

Manoharan

Bobby

Dorairajan

et al. 2020

Exp Clin Endocrinol Diabetes

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Introduction Gestational diabetes mellitus (GDM) exhibit altered placental lipid metabolism. The molecular basis of this altered metabolism is not clear. Altered placental expression of proteins of lipogenesis and fatty acid oxidation may be involved in the placental accumulation of triacylglycerols (TG). The present study was aimed at investigating the differential expressions of placental proteins related to lipid metabolism among GDM women in comparison with control pregnant women (CPW) and to correlate them with maternal and fetal lipid parameters as well as altered fetal growth. Materials and Methods Maternal blood, cord blood, and placental samples were collected from GDM and CPW. The biochemical parameters, glucose, lipid profile and free fatty acids (FFA) were measured. The placental TG content was measured. Differential placental expressions of proteins; phosphatidylinositol-3-kinase (PI3K) p85α, PI3K p110α,liver X receptor alpha (LXRα), sterol regulatory element binding protein1(SREBP1), fatty acid synthase (FAS), stearyl CoA desaturase1 (SCD1), lipoprotein lipase (LPL),Peroxisome proliferator-activated receptor (PPAR)α and PPARγ were analysed by western blotting and immunohistochemistry. Results Placental protein expressions of PI3K p110α, LXRα, FAS, SCD1, and LPL were found to be significantly higher, whereas PPARα and PPARγ were lower in GDM women compared with CPW. The placental TG content and cord plasma FFA were increased in GDM women compared with CPW. The placental TG content positively correlated with Ponderal index of GDM new-borns. Conclusion Differential expressions of placental proteins related to lipid metabolism in GDM might have led to placental TG accumulation. This might have contributed to the fetal overgrowth in GDM.

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“…Despite these findings, little progress has been made therapeutically in targeting enzymes reported to regulate glucose metabolism in GBM.The interconnection between oncogenic signaling networks and metabolic pathways is complex in GBM. For example, while EGFR and PTEN mutations affect PI3K/Akt/mTOR activation, a major contributor to "glucose addiction", this signaling node also acts as a master regulator for switching between metabolic utilization of glucose, glutamine, fatty acids, and ketones 7,8,9,10 . Mutations in isocitrate dehydrogenases (IDH) 1 and 2 are also commonly found in gliomas.…”

mentioning

confidence: 99%

Glioblastoma utilizes fatty acids and ketone bodies for growth allowing progression during ketogenic diet therapy

Sperry

Condro²,

Guo

et al. 2019

Preprint

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Glioblastoma (GBM) metabolism has traditionally been characterized by a dependence on aerobic glycolysis, prompting use of the ketogenic diet as a potential therapy. We observed growth-promoting effects on U87 GBM of both ketone body and fatty acid (FA) supplementation under physiological glucose conditions. An in vivo assessment of the unrestricted ketogenic diet surprisingly resulted in increased tumor growth and decreased animal survival. These effects are abrogated by FAO inhibition using knockdown of carnitine palmitoyltransferase 1 (CPT1).Primary patient GBM cultures revealed significant utilization of FAO regardless of tumorigenic mutational status and decreased proliferation, increased apoptosis, and elevated mitochondrial ROS production with CPT1 inhibition. Metabolomic tracing with 13 C-labeled fatty acids showed significant FA utilization within the TCA cycle, indicating that FAO is used for both bioenergetics and production of key intermediates. These data demonstrate important roles for FA and ketone body metabolism that could serve to improve targeted therapies in GBM.traditionally characterized by its reliance on the Warburg effect. Under normal physiological conditions the healthy adult brain meets most of its energy demand by complete oxidation of glucose. This produces pyruvate which is then converted into acetyl-CoA for entrance into the TCA cycle to support the electron transport chain 1 . Thus, glycolysis and respiration remain tightly connected and result in more efficient ATP production with little lactic acid production. In contrast, the Warburg effect dramatically increases the rate of aerobic glycolysis and lactic acid production in the cytosol. While the benefits of this phenomenon are not completely understood, it has been posited that its main advantages are increased biomass production and facilitated invasion due to acidification of the microenvironment 2 .GBMs have been identified as highly reliant on aerobic glycolysis to the point that they are sometimes referred to as being "glucose addicted". Several common signaling pathways found to be altered in GBM, such as PI3K-Akt-mTOR and Myc pathways, promote this phenotype by increasing expression of genes that allow cells to take up large amounts of glucose for increased glycolysis and lactate production 1, 3, 4 . Alterations to these pathways are often associated with mutations common to GBM such as EGFR and PTEN. EGFR, an activator of PI3K, is amplified in ~40% of GBMs with approximately half of those tumors expressing the constitutively active EGFRviii variant 5 . The tumor suppressor protein PTEN, a potent PI3K antagonist, is also altered in 30-40% of GBMs 6 . Similar to EGFR amplification, loss of PTEN function by either mutation or deletion results in hyperactivation of the PI3K/Akt signaling network. Despite these findings, little progress has been made therapeutically in targeting enzymes reported to regulate glucose metabolism in GBM.The interconnection between oncogenic signaling networks and metabolic pathways is complex in...

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Effects of inhibiting PI3K-Akt-mTOR pathway on lipid metabolism homeostasis in goose primary hepatocytes

Cited by 56 publications

References 33 publications

p110γ deficiency protects against pancreatic carcinogenesis yet predisposes to diet-induced hepatotoxicity

p110γ deficiency protects against pancreatic carcinogenesis yet predisposes to diet-induced hepatotoxicity

Placental Accumulation of Triacylglycerols in Gestational Diabetes Mellitus and Its Association with Altered Fetal Growth are Related to the Differential Expressions of Proteins of Lipid Metabolism

Glioblastoma utilizes fatty acids and ketone bodies for growth allowing progression during ketogenic diet therapy

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