Fatty acid mobilization from adipose tissue is mediated by CD36 posttranslational modifications and intracellular trafficking

Daquinag, Alexes C.; Gao, Zhan‐Guo; Fussell, Cale; Immaraj, Linnet; Pasqualini, Renata; Arap, Wadih; Akimzhanov, Askar M.; Febbraio, Maria; Kolonin, Mikhail G.

doi:10.1172/jci.insight.147057

Cited by 55 publications

(33 citation statements)

References 76 publications

(171 reference statements)

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“…The potential explanation for this is that CD36 regulates MMP28 primarily via intracellular mechanisms independent of its function as a FA transporter. Indeed, several studies showed that besides functioning on the membrane as a FA transporter, CD36 may play other roles such as facilitating intracellular traffic of FAs and increasing the rate of intracellular esterification and, thus, regulating cellular signaling and metabolism without catalyzing the translocation of FAs across the plasma membrane [ 54 , 55 , 56 ]. To support the intracellular role of CD36, our published work shows a significant increase in cytosolic CD36 staining in tumor tissues as compared to normal mucosa [ 15 ].…”

Section: Discussionmentioning

confidence: 99%

Upregulation of CD36, a Fatty Acid Translocase, Promotes Colorectal Cancer Metastasis by Increasing MMP28 and Decreasing E-Cadherin Expression

Drury

Rychahou

Kelson

et al. 2022

Cancers

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Altered fatty acid metabolism continues to be an attractive target for therapeutic intervention in cancer. We previously found that colorectal cancer (CRC) cells with a higher metastatic potential express a higher level of fatty acid translocase (CD36). However, the role of CD36 in CRC metastasis has not been studied. Here, we demonstrate that high expression of CD36 promotes invasion of CRC cells. Consistently, CD36 promoted lung metastasis in the tail vein model and GI metastasis in the cecum injection model. RNA-Seq analysis of CRC cells with altered expression of CD36 revealed an association between high expression of CD36 and upregulation of MMP28, a novel member of the metallopeptidase family of proteins. Using shRNA-mediated knockdown and overexpression of CD36, we confirmed that CD36 regulates MMP28 expression in CRC cells. siRNA-mediated knockdown of MMP28 decreases invasion of CRC cells, suggesting that MMP28 regulates the metastatic properties of cells downstream of CD36. Importantly, high expression of MMP28 leads to a significant decrease in active E-cadherin and an increase in the products of E-cadherin cleavage, CTF1 and CTF2. In summary, upregulation of CD36 expression promotes the metastatic properties of CRC via upregulation of MMP28 and an increase in E-cadherin cleavage, suggesting that targeting the CD36–MMP28 axis may be an effective therapeutic strategy for CRC metastasis.

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Section: Discussionmentioning

confidence: 99%

Upregulation of CD36, a Fatty Acid Translocase, Promotes Colorectal Cancer Metastasis by Increasing MMP28 and Decreasing E-Cadherin Expression

Drury

Rychahou

Kelson

et al. 2022

Cancers

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“…Moreover, VEGF-B is co-expressed with mitochondrial proteins to coordinate FA β-oxidation in adipocytes and reduce the lipid accumulation in adipocytes [ 43 ]. Recently, a low-density lipoprotein receptor-related protein 1 (LRP1) was reported to induce lipogenesis by activating PPARγ signalling in white adipocytes [ 44 , 45 ]. The molecular mechanism of AdECs for controlling lipid catabolism was also demonstrated to involve endothelin-1, which, as an angiogenesis inhibitor, could suppress hormone-sensitive lipase-mediated lipolysis of adipocytes [ 46 , 47 ].…”

Section: Adecs: the Gatekeeper Of Adipocyte Metabolismmentioning

confidence: 99%

Adipose endothelial cells mastering adipose tissues metabolic fate

Liao

Ran

et al. 2022

Adipocyte

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Dynamic communication within adipose tissue depends on highly vascularized structural characteristics to maintain systemic metabolic homoeostasis. Recently, it has been noted that adipose endothelial cells (AdECs) act as essential bridges for biological information transmission between adipose-resident cells. Hence, paracrine regulators that mediate crosstalk between AdECs and adipose stromal cells were summarized. We also highlight the importance of AdECs to maintain adipocytes metabolic homoeostasis by regulating insulin sensitivity, lipid turnover and plasticity. The differential regulation of AdECs in adipose plasticity often depends on vascular density and metabolic states. Although choosing pro-angiogenic or anti-angiogenic therapies for obesity is still a matter of debate in clinical settings, the growing numbers of drugs have been confirmed to play an anti-obesity effect by affecting vascularization. Pharmacologic angiogenesis intervention has great potential as therapeutic strategies for obesity.

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“…It facilitates fatty acid (FA) transport into white and brown adipose tissue, heart and skeletal muscle, but the mechanism is not well-understood (12). Recent data also suggest a role in dermal albumin transcytosis, adipocyte FA export, and in tumor growth and metastasis (13)(14)(15)(16). Structurally, CD36 has two transmembrane domains that terminate with very short intracellular domains (17).…”

Section: Introductionmentioning

confidence: 99%

Endothelial Cell CD36 Reduces Atherosclerosis and Controls Systemic Metabolism

Rekhi

Omar

Alexiou

et al. 2021

Front. Cardiovasc. Med.

Self Cite

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High-fat Western diets contribute to tissue dysregulation of fatty acid and glucose intake, resulting in obesity and insulin resistance and their sequelae, including atherosclerosis. New therapies are desperately needed to interrupt this epidemic. The significant idea driving this research is that the understudied regulation of fatty acid entry into tissues at the endothelial cell (EC) interface can provide novel therapeutic targets that will greatly modify health outcomes and advance health-related knowledge. Dysfunctional endothelium, defined as activated, pro-inflammatory, and pro-thrombotic, is critical in atherosclerosis initiation, in modulating thrombotic events that could result in myocardial infarction and stroke, and is a hallmark of insulin resistance. Dyslipidemia from high-fat diets overwhelmingly contributes to the development of dysfunctional endothelium. CD36 acts as a receptor for pathological ligands generated by high-fat diets and in fatty acid uptake, and therefore, it may additionally contribute to EC dysfunction. We created EC CD36 knockout (CD36°) mice using cre-lox technology and a cre-promoter that does not eliminate CD36 in hematopoietic cells (Tie2e cre). These mice were studied on different diets, and crossed to the low density lipoprotein receptor (LDLR) knockout for atherosclerosis assessment. Our data show that EC CD36° and EC CD36°/LDLR° mice have metabolic changes suggestive of an uncompensated role for EC CD36 in fatty acid uptake. The mice lacking expression of EC CD36 had increased glucose clearance compared with controls when fed with multiple diets. EC CD36° male mice showed increased carbohydrate utilization and decreased energy expenditure by indirect calorimetry. Female EC CD36°/LDLR° mice have reduced atherosclerosis. Taken together, these data support a significant role for EC CD36 in systemic metabolism and reveal sex-specific impact on atherosclerosis and energy substrate use.

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Fatty acid mobilization from adipose tissue is mediated by CD36 posttranslational modifications and intracellular trafficking

Cited by 55 publications

References 76 publications

Upregulation of CD36, a Fatty Acid Translocase, Promotes Colorectal Cancer Metastasis by Increasing MMP28 and Decreasing E-Cadherin Expression

Upregulation of CD36, a Fatty Acid Translocase, Promotes Colorectal Cancer Metastasis by Increasing MMP28 and Decreasing E-Cadherin Expression

Adipose endothelial cells mastering adipose tissues metabolic fate

Endothelial Cell CD36 Reduces Atherosclerosis and Controls Systemic Metabolism

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