Fatty Acid Uptake and Lipid Storage Induced by HIF-1α Contribute to Cell Growth and Survival after Hypoxia-Reoxygenation

Bensaad, Karim; Favaro, Elena; Lewis, Caroline A.; Peck, Barrie; Lord, Simon; Collins, Jennifer; Pinnick, Katherine E.; Wigfield, Simon; Buffa, Francesca M.; Li, Jiliang; Zhang, Zuo‐Feng; Wakelam, Michael J.O.; Karpe, Fredrik; Schulze, Almut; Harris, Adrian L.

doi:10.1016/j.celrep.2014.08.056

Cited by 554 publications

(531 citation statements)

References 62 publications

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“…It has been also reported that tendon retraction in full‐thickness medium‐sized RCT is characterized by neovascularity, increased VEGF/HIF expression, fatty infiltration, and muscle atrophy,40 showing substantial involvement of HIF1 in RCT. In addition, a recent study demonstrated that FABP3 and FABP7 are induced by HIF‐1α and lead to a significant lipid droplet accumulation in hypoxia 47. Together with our present finding, these evidences indicate that RCT‐induced hypoxic condition activates HIF1 and further regulates FABP expression ( Figure 6).…”

Section: Discussionsupporting

confidence: 89%

Fatty acid‐binding protein 4 regulates fatty infiltration after rotator cuff tear by hypoxia‐inducible factor 1 in mice

Lee

Kim

et al. 2017

J cachexia sarcopenia muscle

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BackgroundFatty infiltration in skeletal muscle is directly linked to loss of muscle strength and is associated with various adverse physical outcomes such as muscle atrophy, inflammation, insulin resistance, mobility impairments, and even mortality in the elderly. Aging, mechanical unloading, muscle injury, and hormonal imbalance are main causes of muscle fat accumulation, and the fat cells are derived from muscle stem cells via adipogenic differentiation. However, the pathogenesis and molecular mechanisms of fatty infiltration in muscles are still not fully defined. Fatty acid‐binding protein 4 (FABP4) is a carrier protein for fatty acids and is involved in fatty acid uptake, transport, and lipid metabolism. Rotator cuff tear (RCT) usually occurs in the elderly and is closely related with fatty infiltration in injured muscle. To investigate potential mechanisms for fatty infiltration other than adipogenic differentiation of muscle stem cells, we examined the role of FABP4 in muscle fatty infiltration in an RCT mouse model.MethodsIn the RCT model, we evaluated the expression of FABP4 by qRT‐PCR, western blotting, and immunohistochemical analyses. Histological changes such as inflammation and fat accumulation in the injured muscles were examined immunohistochemically. To evaluate whether hypoxia induces FABP4 expression, the levels of FABP4 mRNA and protein in C3H10T1/2 cells after hypoxia were examined. Using a transient transfection assay in 293T cells, we assessed the promoter activity of FABP4 by hypoxia‐inducible factors (HIFs). Additionally, we evaluated the reduction in FABP4 expression and fat accumulation using specific inhibitors for HIF1 and FABP4, respectively.ResultsFABP4 expression was significantly increased after RCT in mice, and its expression was localized in the intramuscular fatty region. Rotator cuff tear‐induced FABP4 expression was up‐regulated by hypoxia. HIF1α, which is activated by hypoxia, augmented the promoter activity of FABP4, together with HIF1β. Hypoxia‐induced FABP4 expression was significantly decreased by HIF1 inhibitor treatment. Furthermore, in RCT model mice, fat accumulation was remarkably reduced by FABP4 inhibitor treatment.ConclusionsThis study shows that RCT induces FABP4 expression, leading to fat accumulation in injured muscle. FABP4 transcription is regulated by the direct binding of HIF1 to the FABP4 promoter in the hypoxic condition induced by RCT. Fat accumulation in injured muscle was reduced by the inhibition of FABP4. Ultimately, in the RCT model, we identified a novel mechanism for fatty infiltration by FABP4, which differs from adipogenic differentiation of muscle stem cells, and we found that fatty infiltration might be regulated by inhibition of HIF1 or FABP4.

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Section: Discussionsupporting

confidence: 89%

Fatty acid‐binding protein 4 regulates fatty infiltration after rotator cuff tear by hypoxia‐inducible factor 1 in mice

Lee

Kim

et al. 2017

J cachexia sarcopenia muscle

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“…Cancer is associated with dysregulated lipid metabolism both at the systemic and paracrine level and intracellular lipid accumulation may promote cancer cell aggressiveness (6,(36)(37)(38). Most studies involve the role of de novo lipogenesis from increased utilization of glucose carbons and autocrine processes, whereas the importance of extracellular lipids of the tumor microenvironment remains relatively ill-defined.…”

Section: Discussionmentioning

confidence: 99%

Metastasis Stimulation by Hypoxia and Acidosis-Induced Extracellular Lipid Uptake Is Mediated by Proteoglycan-Dependent Endocytosis

et al. 2016

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Hypoxia and acidosis are inherent stress factors of the tumor microenvironment and have been linked to increased tumor aggressiveness and treatment resistance. Molecules involved in the adaptive mechanisms that drive stress-induced disease progression constitute interesting candidates of therapeutic intervention. Here, we provide evidence of a novel role of heparan sulfate proteoglycans (HSPG) in the adaptive response of tumor cells to hypoxia and acidosis through increased internalization of lipoproteins, resulting in a lipid-storing phenotype and enhanced tumor-forming capacity. Patient glioblastoma tumors and cells under hypoxic and acidic stress acquired a lipid droplet (LD)-loaded phenotype, and showed an increased recruitment of all major lipoproteins, HDL, LDL, and VLDL. Stress-induced LD accumulation was associated with increased spheroid-forming capacity during reoxygenation in vitro and lung metastatic potential in vivo. On a mechanistic level, we found no apparent effect of hypoxia on HSPGs, whereas lipoprotein receptors (VLDLR and SR-B1) were transiently upregulated by hypoxia. Importantly, however, using pharmacologic and genetic approaches, we show that stress-mediated lipoprotein uptake is highly dependent on intact HSPG expression. The functional relevance of HSPG in the context of tumor cell stress was evidenced by HSPG-dependent lipoprotein cell signaling activation through the ERK/MAPK pathway and by reversal of the LD-loaded phenotype by targeting of HSPGs. We conclude that HSPGs may have an important role in the adaptive response to major stress factors of the tumor microenvironment, with functional consequences on tumor cell signaling and metastatic potential. Cancer Res; 76(16); 4828-40. Ó2016 AACR.

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“…Hypoxia enhances aggressive tumor attributes but correlates negatively with a decrease in outcome [22]. Fatty acid uptake and lipid storage are enhanced by hypoxia-inducible factor 1 alpha and may contribute to tumor cell growth after hypoxia-reoxygenation [23].…”

Section: Constitutional Attributesmentioning

confidence: 99%

Dual Parallel Sequence Progression as Vascular Pseudo-Reactivities to Tumor Necrosis and to Proliferation of Glioblastoma Cells

Agius¹

2016

J Carcinog Mutagen

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Directional projections of glioblastoma biology include the constitutive clonality of a lesion that infiltrates in terms of its established potential proliferation involving predominantly poorly differentiated cell populations. In large measure, inclusive parameters correlate with the presence of contrastingly different types of genetic lesion, such as for example, the implication of p53 mutation versus the amplification/over-expression of the Epidermal Growth Factor Receptor (EGFR) in the neoplastic cells. Involvement of vasculature and of intense vascularization of multiple foci of the evolving glioblastoma emphasizes the distinctive link to multiple foci of tumor necrosis. Collaborative features include also an apparent propensity for pseudo-multifocality arising from processes of highly active foci of infiltration within the white matter. Cancer stem cells are believed to be the propagating cell component in gliomas and may differ from glioma initiating cells responsible for the establishment and survival of the neoplasm. Therapeutic resistance may specifically relate to resistance of the glioma stem cells that are found in small numbers in the tumor. Patient age is a distinctive feature of glioblastoma that progresses in close parallel with the vasculogenesis in neoplastic cell infiltration of adjacent tracts such as the corpus callosum and also the cerebral white matter of one or both cerebral hemispheres.

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Fatty Acid Uptake and Lipid Storage Induced by HIF-1α Contribute to Cell Growth and Survival after Hypoxia-Reoxygenation

Cited by 554 publications

References 62 publications

Fatty acid‐binding protein 4 regulates fatty infiltration after rotator cuff tear by hypoxia‐inducible factor 1 in mice

Fatty acid‐binding protein 4 regulates fatty infiltration after rotator cuff tear by hypoxia‐inducible factor 1 in mice

Metastasis Stimulation by Hypoxia and Acidosis-Induced Extracellular Lipid Uptake Is Mediated by Proteoglycan-Dependent Endocytosis

Dual Parallel Sequence Progression as Vascular Pseudo-Reactivities to Tumor Necrosis and to Proliferation of Glioblastoma Cells

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