PTEN Down-Regulation by Unsaturated Fatty Acids Triggers Hepatic Steatosis via an NF-κBp65/mTOR-Dependent Mechanism

Vinciguerra, Manlio; Veyrat-Durebex, Christelle; Moukil, Moulay Ahmed; Rubbia‐Brandt, Laura; Rohner‐Jeanrenaud, Françoise; Foti, Michelangelo

doi:10.1053/j.gastro.2007.10.010

Cited by 132 publications

(152 citation statements)

References 31 publications

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“…The RNA level of HOTAIR was upregulated in all groups of cells treated with FFAs (all P < 0.05) (Figure 1(c)). And consistent with previous studies [19], PTEN mRNA and protein levels were decreased in the cells treated with 50 µM OA or LA; in addition, PA, PA/OA, or PA/OA# also resulted in down-regulation of PTEN mRNA and protein levels (all P < 0.05) (Figure 1(c,d)). …”

Section: Ffa Treatment Promotes Triglyceride Accumulation In Hepg2 Cesupporting

confidence: 91%

“…It is usually down-regulated in patients and rodent models with NAFLD and HCC [13][14][15][16]. Vinciguerra et al [19,20] showed that PTEN down-regulation induced by unsaturated FFAs could accelerate triglyceride accumulation in hepatocytes, and promotes hepatoma proliferation and progression. Accordingly, the present study showed that PTEN was down-regulated in HepG2 cells exposed to FFAs, further supporting the modeling of HepG2 cells into a model of NAFLD upon treatment of PA and OA.…”

Section: Discussionmentioning

confidence: 99%

“…Hepatocyte-specific null mutation of PTEN in mice leads to massive hepatomegaly and steatohepatitis with triglyceride accumulation, and later to HCC [17,18]. PTEN expression is also down-regulated in cultured hepatocytes exposed to FFAs, and PTEN expression inhibited by FFAs could trigger hepatic steatosis via an NFκB/mTOR-dependent pathway [19]. Dietary unsaturated fatty acids promote the growth ability and metastatic capacity of HepG2 cells by suppressing PTEN, and the effects were prevented by NF-κB inhibitor [20].…”

Section: Introductionmentioning

confidence: 99%

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Up-regulated HOTAIR induced by fatty acids inhibits PTEN expression and increases triglycerides accumulation in HepG2 cells

Chen

Lin

et al. 2017

Food & Nutrition Research

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Non-alcoholic fatty liver disease (NAFLD) is characterized by hepatic lipid accumulation unrelated to excess alcohol intake, in which the hepatic expression of phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is inhibited. Long non-coding RNA HOTAIR suppresses PTEN expression in hepatic stellate cells during liver fibrosis, and it is involved in liver lipid dysregulation. In this study, we evaluated whether the PTEN down-regulation and lipid accumulation in hepatic cells might be mediated by HOTAIR during the development of NAFLD. Free fatty acids (FFAs) treatment promoted triglyceride accumulation in HepG2 cells, significantly increasing HOTAIR expression and inhibiting PTEN expression (both at mRNA and protein levels).The effects on HOTAIR and PTEN expressions disappeared after withdrawal of the FFAs treatment. SiRNAmediated HOTAIR knockdown prevented PTEN down-regulation and triglyceride accumulation in HepG2 cells treated with FFAs; and CAPE (an NF-κBp65 inhibitor) treatment prevented the HOTAIR up-regulation and PTEN down-regulation. FFAs could induce the up-regulation of HOTAIR in HepG2 cells probably dependent on the NF-κB signaling, and consequently suppress PTEN expression and promote triglyceride accumulation. Aberrant up-regulation of HOTAIR mediated by excessive circulating FFAs levels may be a crucial mechanism associated with liver steatosis. ARTICLE HISTORY

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Section: Ffa Treatment Promotes Triglyceride Accumulation In Hepg2 Cesupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Up-regulated HOTAIR induced by fatty acids inhibits PTEN expression and increases triglycerides accumulation in HepG2 cells

Chen

Lin

et al. 2017

Food & Nutrition Research

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“…Fatty acids have been reported to regulate Akt activity in a PTEN-dependent or -independent manner (34). For example, in vascular endothelial cells, palmitic acid inhibited basal Akt phosphorylation and insulin-stimulated Akt phosphorylation by increasing PTEN transcription (35).…”

Section: Discussionmentioning

confidence: 99%

Subcutaneous Adipocytes Promote Melanoma Cell Growth by Activating the Akt Signaling Pathway

Kwan

Liu

et al. 2014

Journal of Biological Chemistry

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Background: Fatty acids affect cancer growth. Results: Melanoma in co-cultivation with subcutaneous adipocytes has an elevated level of palmitic acid that promotes melanoma growth by activating Akt signaling in a PTEN-independent manner. Conclusion: Subcutaneous adipocytes may be an exogenous source of palmitic acid for melanoma growth. Significance: Targeting an exogenous supply of palmitic acid suggests a novel therapeutic in melanoma treatment.

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“…However, adding to the complexity of PTEN function, transgenic mice, overexpressing PTEN, display increased energy expenditure and insulin sensitivity [11,12]. Regarding the liver, we previously reported that PTEN is downregulated in steatotic livers of obese patients, as well as in rat models of genetic or diet-induced obesity [13]. Likewise, PTEN is downregulated in the liver of patients infected with hepatitis C virus (HCV) [14].…”

Section: Introductionmentioning

confidence: 99%

Hepatic PTEN deficiency improves muscle insulin sensitivity and decreases adiposity in mice

Peyrou

Bourgoin

Poher

et al. 2015

Journal of Hepatology

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Background & Aims: PTEN is a dual lipid/protein phosphatase, downregulated in steatotic livers with obesity or HCV infection. Liver-specific PTEN knockout (LPTEN KO) mice develop steatosis, inflammation/fibrosis and hepatocellular carcinoma with aging, but surprisingly also enhanced glucose tolerance. This study aimed at understanding the mechanisms by which hepatic PTEN deficiency improves glucose tolerance, while promoting fatty liver diseases. Methods: Control and LPTEN KO mice underwent glucose/pyruvate tolerance tests and euglycemic-hyperinsulinemic clamps. Body fat distribution was assessed by EchoMRI, CT-scan and dissection analyses. Primary/cultured hepatocytes and insulin-sensitive tissues were analysed ex vivo. Results: PTEN deficiency in hepatocytes led to steatosis through increased fatty acid (FA) uptake and de novo lipogenesis. Although LPTEN KO mice exhibited hepatic steatosis, they displayed increased skeletal muscle insulin sensitivity and glucose uptake, as assessed by euglycemic-hyperinsulinemic clamps. Surprisingly, white adipose tissue (WAT) depots were also drastically reduced. Analyses of key enzymes involved in lipid metabolism further indicated that FA synthesis/esterification was decreased in WAT. In addition, Ucp1 expression and multilocular lipid droplet structures were observed in this tissue, indicating the presence of beige adipocytes. Consistent with a liver to muscle/ adipocyte crosstalk, the expression of liver-derived circulating factors, known to impact on muscle insulin sensitivity and WAT homeostasis (e.g. FGF21), was modulated in LPTEN KO mice.

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PTEN Down-Regulation by Unsaturated Fatty Acids Triggers Hepatic Steatosis via an NF-κBp65/mTOR-Dependent Mechanism

Abstract: Hepatic steatosis can be mediated by alterations of PTEN expression in hepatocytes exposed to high levels of unsaturated fatty acids. Furthermore, our data revealed interaction between mTOR and NF-kappaB, suggesting cross-talk between these 2 pathways.

Cited by 132 publications

References 31 publications

Up-regulated HOTAIR induced by fatty acids inhibits PTEN expression and increases triglycerides accumulation in HepG2 cells

Up-regulated HOTAIR induced by fatty acids inhibits PTEN expression and increases triglycerides accumulation in HepG2 cells

Subcutaneous Adipocytes Promote Melanoma Cell Growth by Activating the Akt Signaling Pathway

Hepatic PTEN deficiency improves muscle insulin sensitivity and decreases adiposity in mice

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