Sustained SREBP-1-dependent lipogenesis as a key mediator of resistance to BRAF-targeted therapy
Ali TalebiJonas DehairsFlorian RambowAljosja RogiersDavid NittnerRita DeruaFrank VanderhoydoncJoão André Gonçalves DuarteFrancesca Maria BosisioKathleen Van den EyndeKris NysMónica Vara‐PérezPatrizia AgostinisEtienne WaelkensJoost van den OordSarah‐Maria FendtJean‐Christophe MarineJohannes V. Swinnen
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Abstract Whereas significant anti-tumor responses are observed in most BRAF V600E -mutant melanoma patients exposed to MAPK-targeting agents, resistance almost invariably develops. Here, we show that in therapy-responsive cells BRAF inhibition induces downregulation of the processing of Sterol Regulator Element Binding (SREBP-1) and thereby lipogenesis. Irrespective of the escape mechanism, therapy-resistant cells invariably restore this process to promote lipid saturation and protect melanoma from ROS-induced damage and lipid peroxidation. Importantly, pharmacological SREBP-1 inhibition sensitizes BRAF V600E -mutant therapy-resistant melanoma to BRAF V600E inhibitors both in vitro and in a pre-clinical PDX in vivo model. Together, these data indicate that targeting SREBP-1-induced lipogenesis may offer a new avenue to overcome acquisition of resistance to BRAF-targeted therapy. This work also provides evidence that targeting vulnerabilities downstream of oncogenic signaling offers new possibilities in overcoming resistance to targeted therapies.Keywords:
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Background/Aims: Sterol regulatory element-binding protein (SREBP) 1, the master regulator of lipogenesis, was shown to be associated with non-alcoholic fatty liver disease, which is attributed to its major isoform SREBP1c. Based on studies in mice, the minor isoform SREBP1a is regarded as negligible for hepatic lipogenesis. This study aims to elucidate the expression and functional role of SREBP1a in human liver. Methods: mRNA expression of both isoforms was quantified in cohorts of human livers and primary human hepatocytes. Hepatocytes were treated with PF-429242 to inhibit the proteolytic activation of SREBP precursor protein. SREBP1a-specifc and pan-SREBP1 knock-down were performed by transfection of respective siRNAs. Lipogenic SREBP-target gene expression was analyzed by real-time RT-PCR. Results: In human liver, SREBP1a accounts for up to half of the total SREBP1 pool. Treatment with PF-429242 indicated SREBP-dependent auto-regulation of SREBP1a, which however was much weaker than of SREBP1c. SREBP1a-specifc knock-down also reduced significantly the expression of SREBP1c and of SREBP-target genes. Regarding most SREBP-target genes, simultaneous knock-down of both isoforms resulted in effects of only similar extent as SREBP1a-specific knock-down. Conclusion: We here showed that SREBP1a is significantly contributing to the human hepatic SREBP1 pool and has a share in human hepatic lipogenic gene expression.
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Sterol regulatory element binding protein- 1 and -2 (SREBP-1 and -2) are key transcription factors involved in the biosynthesis of cholesterol and fatty acids. The SREBP have mostly been studied in rodents in which lipogenesis is regulated in both liver and adipose tissue. There is, though, a paucity of information on birds, in which lipogenesis occurs essentially in the liver as in humans. Since a prelude to the investigation of the role of SREBP in lipid metabolism regulation in chicken, we review Size and Tissue expression Pattern of SREBP and role of this protein in chickens.
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Stearoyl-CoA desaturase-1 (SCD1) is a key player in lipid metabolism. SCD1 catalyzes the synthesis of monounsaturated fatty acids (MUFA). MUFA are then incorporated into triacylglycerols and phospholipids. Previous studies have shown that Scd1 deficiency in mice induces metabolic changes in the liver characterized by a decrease in de novo lipogenesis and an increase in β-oxidation. Interestingly, Scd1-deficient mice show a decrease in the expression and maturation of the principal lipogenic transcription factor sterol receptor element binding protein-1 (SREBP-1). The mechanisms mediating this effect on de novo lipogenesis and β-oxidation have not been fully elucidated. We evaluated the role of SCD1 on de novo lipogenesis and β-oxidation in HepG2 cells. We also used Scd1-deficient mice and two strains of transgenic mice that produce either oleate (GLS5) or palmitoleate (GLS3) in a liver-specific manner. We demonstrate that the expression of β-oxidation markers increases in SCD1-deficient hepatocytes and suggest that this is due to an increase in cellular polyunsaturated fatty acid content. We also show that the changes in the level of SREBP-1 expression, for both the precursor and the mature forms, are mainly due to the lack of oleate in SCD1-deficient hepatocytes. Indeed, oleate treatment of cultured HepG2 cells or hepatic oleate production in chow-fed GLS5 mice can restore SREBP-1 expression and increase hepatic de novo lipogenesis. Finally, we show that oleate specifically increases SREBP-1 nuclear accumulation, suggesting a central role for oleate in SREBP-1 signaling activity.
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Fatty acid synthase (FAS), a key lipogenic enzyme, is expressed in the two major sites of fatty acid production in the body, that is, the liver and the adipose tissue. Surprisingly, the relative contribution of these sites to lipogenesis is highly variable among species. For example, besides the situation in rodents, where liver and fat are equally active, lipogenesis in some mammals such as the pig occurs principally in adipose tissue, whereas in avian species, the liver is the main lipogenic site. We addressed the question concerning the factors determining the site of fatty acid synthesis. We show that the expression of adipocyte determination and differentiation-dependent factor 1/sterol regulatory element-binding protein (ADD-1/SREBP-1) mRNA, but not SREBP-2, is linked to FAS protein content or activity in adipose tissues and livers of pig, chicken, and rabbit. Tissue differences in ADD-1/SREBP-1 mRNA expression between species were paralleled by commensurate variations in the nuclear concentration of SREBP-1 protein. Moreover, overexpression of ADD-1/SREBP-1 by adenoviral gene transfer induces FAS in chicken adipocytes, where lipogenesis is normally low. Conversely, the expression of a dominant negative form of ADD-1/SREBP-1 in pig adipocytes downregulates FAS expression. These results reinforce the role of ADD-1/SREBP-1 as a key regulator of lipogenesis, by extending its importance to nonrodent mammals and birds. Furthermore, they establish that differential expression of ADD-1/SREBP-1 is a key determinant of the site of fatty acid synthesis in the body.—Gondret, F., P. Ferré, and I. Dugail. ADD-1/SREBP-1 is a major determinant of tissue differential lipogenic capacity in mammalian and avian species. J. Lipid Res. 2001. 42: 106–113.
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Stearoyl‐CoA desaturase (SCD) catalyzes the de novo synthesis of monounsaturated fatty acids (MUFA) from saturated fatty acid precursors. Previous work has demonstrated that SCD1 deficiency impairs hepatic lipogenesis and protects against development of diet‐induced obesity. The objective of this study was to determine if liver‐specific MUFA synthesis restores hepatic lipogenesis and processing of the sterol regulatory element binding protein‐1 (SREBP‐1) in SCD1 global knockout mice (GKO). We produced transgenic mice expressing human SCD5 only in liver and introduced this transgene into GKO mice. Hepatic SREBP‐1 maturation is increased in the hSCD5/GKO mice while increased expression of several important lipogenic genes also occurs. Unlike GKO mice fed a high carbohydrate, very low fat diet, hSCD5/GKO mice are largely protected from the dramatic weight loss that occurs. These results suggest that the product of the reaction catalyzed by hSCD5, 18:1n‐9, is involved in the regulation of SREBP‐1 processing as well as lipogenesis. Supported by NIH.
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Metabolic rewiring is one of the hallmarks of cancer. Altered de novo lipogenesis is one of the pivotal metabolic events deregulated in cancers. Sterol regulatory element-binding transcription factor 1 (SREBP1) controls the transcription of major enzymes involved in de novo lipogenesis, including ACLY, ACACA, FASN, and SCD. Studies have shown the increased de novo lipogenesis in human hepatocellular carcinoma (HCC) samples. Multiple mechanisms, such as activation of the AKT/mechanistic target of rapamycin (mTOR) pathway, lead to high SREBP1 induction and the coordinated enhanced expression of
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Sterol regulatory element binding proteins (SREBPs) are a family of transcription factors that regulate lipid metabolism. There are 3 isoforms, SREBP-1a, SREBP-1c and SREBP-2, among which SREBP-1a and SREBP-1c regulate fatty acid synthesis. The objective of this study was to determine the role of SREBP-1 in lipogenesis in bovine mammary epithelial cells. Bovine mammary epithelial cells (MACT) were used in this study. After reaching 80% confluence in a flask, cells were reseeded to plates at a density of 2X104 cells/cm2. After overnight, cells were transfected using small interfering RNAs (siRNA), against SREBP-1 (SSI), a non-targeting sequence as negative control (NEG), and no siRNA as untreated control (UNT), according to protocol (Dharmacon Inc.). Cells were harvested for measurement of mRNA, protein and acetate incorporation after 48 h. SSI reduced SREBP-1 mRNA and protein by 76% and 98%. De novo lipogenic gene mRNA decreased almost 50% (P<0.01). Acetate incorporation also decreased significantly with SSI (P < 0.01). When SREBP-1 decreased, there was a reduction in de novo lipogenic genes and acetate incorporation, thus SREBP-1 might regulate milk fat through the de novo fatty acid synthesis pathway. This project was supported by National Research Initiative Competitive Grant no. 2009-35204-05358 from the USDA National Institute of Food and Agriculture.
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