Publications by authors named "Dmitri Samovski"

15 Publications

  • Page 1 of 1

Lipolytic enzymes and free fatty acids at the endothelial interface.

Atherosclerosis 2021 Jul 28;329:1-8. Epub 2021 May 28.

Department of Medicine, Center for Human Nutrition, Washington University School of Medicine, Saint Louis, MO, USA. Electronic address:

Lipids released from circulating lipoproteins by intravascular action of lipoprotein lipase (LpL) reach parenchymal cells in tissues with a non-fenestrated endothelium by transfer through or around endothelial cells. The actions of LpL are controlled at multiple sites, its synthesis and release by myocytes and adipocytes, its transit and association with the endothelial cell luminal surface, and finally its activation and inhibition by a number of proteins and by its product non-esterified fatty acids. Multiple pathways mediate endothelial transit of lipids into muscle and adipose tissues. These include movement of fatty acids via the endothelial cell fatty acid transporter CD36 and movement of whole or partially LpL-hydrolyzed lipoproteins via other apical endothelial cell receptors such as SR-B1and Alk1. Lipids also likely change the barrier function of the endothelium and operation of the paracellular pathway around endothelial cells. This review summarizes in vitro and in vivo support for the key role of endothelial cells in delivery of lipids and highlights incompletely understood processes that are the focus of active investigation.
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http://dx.doi.org/10.1016/j.atherosclerosis.2021.05.018DOI Listing
July 2021

Associations Among Adipose Tissue Immunology, Inflammation, and Exosomes and Insulin Sensitivity in People With Obesity and Nonalcoholic Fatty Liver Disease.

Gastroenterology 2021 May 15. Epub 2021 May 15.

Center for Human Nutrition, Washington University School of Medicine, St. Louis, Missouri. Electronic address:

Background And Aims: Insulin resistance is a key factor in the pathogenesis of nonalcoholic fatty liver disease (NAFLD). We evaluated the importance of subcutaneous abdominal adipose tissue (SAAT) inflammation and both plasma and SAAT-derived exosomes in regulating insulin sensitivity in people with obesity and NAFLD.

Methods: Adipose tissue inflammation (macrophage and T-cell content and expression of proinflammatory cytokines), liver and whole-body insulin sensitivity (assessed using a hyperinsulinemic-euglycemic clamp and glucose tracer infusion), and 24-hour serial plasma cytokine concentrations were evaluated in 3 groups stratified by adiposity and intrahepatic triglyceride (IHTG) content: (1) lean with normal IHTG content (LEAN; n = 14); (2) obese with normal IHTG content (OB-NL; n = 28); and (3) obese with NAFLD (OB-NAFLD; n = 28). The effect of plasma and SAAT-derived exosomes on insulin-stimulated Akt phosphorylation in human skeletal muscle myotubes and mouse primary hepatocytes was assessed in a subset of participants.

Results: Proinflammatory macrophages, proinflammatory CD4 and CD8 T-cell populations, and gene expression of several cytokines in SAAT were greater in the OB-NAFLD than the OB-NL and LEAN groups. However, with the exception of PAI-1, which was greater in the OB-NAFLD than the LEAN and OB-NL groups, 24-hour plasma cytokine concentration areas-under-the-curve were not different between groups. The percentage of proinflammatory macrophages and plasma PAI-1 concentration areas-under-the-curve were inversely correlated with both hepatic and whole-body insulin sensitivity. Compared with exosomes from OB-NL participants, plasma and SAAT-derived exosomes from the OB-NAFLD group decreased insulin signaling in myotubes and hepatocytes.

Conclusions: Systemic insulin resistance in people with obesity and NAFLD is associated with increased plasma PAI-1 concentrations and both plasma and SAAT-derived exosomes. ClinicalTrials.gov number: NCT02706262.
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http://dx.doi.org/10.1053/j.gastro.2021.05.008DOI Listing
May 2021

Endothelial Cell Receptors in Tissue Lipid Uptake and Metabolism.

Circ Res 2021 02 4;128(3):433-450. Epub 2021 Feb 4.

Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, New York University Grossman School of Medicine (A.G.C., D.B., I.J.G.).

Lipid uptake and metabolism are central to the function of organs such as heart, skeletal muscle, and adipose tissue. Although most heart energy derives from fatty acids (FAs), excess lipid accumulation can cause cardiomyopathy. Similarly, high delivery of cholesterol can initiate coronary artery atherosclerosis. Hearts and arteries-unlike liver and adrenals-have nonfenestrated capillaries and lipid accumulation in both health and disease requires lipid movement from the circulation across the endothelial barrier. This review summarizes recent in vitro and in vivo findings on the importance of endothelial cell receptors and uptake pathways in regulating FAs and cholesterol uptake in normal physiology and cardiovascular disease. We highlight clinical and experimental data on the roles of ECs in lipid supply to tissues, heart, and arterial wall in particular, and how this affects organ metabolism and function. Models of FA uptake into ECs suggest that receptor-mediated uptake predominates at low FA concentrations, such as during fasting, whereas FA uptake during lipolysis of chylomicrons may involve paracellular movement. Similarly, in the setting of an intact arterial endothelial layer, recent and historic data support a role for receptor-mediated processes in the movement of lipoproteins into the subarterial space. We conclude with thoughts on the need to better understand endothelial lipid transfer for fuller comprehension of the pathophysiology of hyperlipidemia, and lipotoxic diseases such as some forms of cardiomyopathy and atherosclerosis.
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http://dx.doi.org/10.1161/CIRCRESAHA.120.318003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7959116PMC
February 2021

Regulation of lipophagy in NAFLD by cellular metabolism and CD36.

J Lipid Res 2019 04 28;60(4):755-757. Epub 2019 Feb 28.

Center for Human Nutrition, Washington University School of Medicine, Saint Louis, MO 63108.

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http://dx.doi.org/10.1194/jlr.C093674DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6446712PMC
April 2019

Endothelial cell CD36 optimizes tissue fatty acid uptake.

J Clin Invest 2018 10 26;128(10):4329-4342. Epub 2018 Jul 26.

Division of Endocrinology, Diabetes and Metabolism, New York University School of Medicine, New York, New York, USA.

Movement of circulating fatty acids (FAs) to parenchymal cells requires their transfer across the endothelial cell (EC) barrier. The multiligand receptor cluster of differentiation 36 (CD36) facilitates tissue FA uptake and is expressed in ECs and parenchymal cells such as myocytes and adipocytes. Whether tissue uptake of FAs is dependent on EC or parenchymal cell CD36, or both, is unknown. Using a cell-specific deletion approach, we show that EC, but not parenchymal cell, CD36 deletion increased fasting plasma FAs and postprandial triglycerides. EC-Cd36-KO mice had reduced uptake of radiolabeled long-chain FAs into heart, skeletal muscle, and brown adipose tissue; these uptake studies were replicated using [11C]palmitate PET scans. High-fat diet-fed EC-CD36-deficient mice had improved glucose tolerance and insulin sensitivity. Both EC and cardiomyocyte (CM) deletion of CD36 reduced heart lipid droplet accumulation after fasting, but CM deletion did not affect heart glucose or FA uptake. Expression in the heart of several genes modulating glucose metabolism and insulin action increased with EC-CD36 deletion but decreased with CM deletion. In conclusion, EC CD36 acts as a gatekeeper for parenchymal cell FA uptake, with important downstream effects on glucose utilization and insulin action.
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http://dx.doi.org/10.1172/JCI99315DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6159965PMC
October 2018

Regulation of Insulin Receptor Pathway and Glucose Metabolism by CD36 Signaling.

Diabetes 2018 07 10;67(7):1272-1284. Epub 2018 May 10.

Departments of Medicine and Cell Biology, Washington University in St. Louis, St. Louis, MO

During reduced energy intake, skeletal muscle maintains homeostasis by rapidly suppressing insulin-stimulated glucose utilization. Loss of this adaptation is observed with deficiency of the fatty acid transporter CD36. A similar loss is also characteristic of the insulin-resistant state where CD36 is dysfunctional. To elucidate what links CD36 to muscle glucose utilization, we examined whether CD36 signaling might influence insulin action. First, we show that CD36 deletion specific to skeletal muscle reduces expression of insulin signaling and glucose metabolism genes. It decreases muscle ceramides but impairs glucose disposal during a meal. Second, depletion of CD36 suppresses insulin signaling in primary-derived human myotubes, and the mechanism is shown to involve functional CD36 interaction with the insulin receptor (IR). CD36 promotes tyrosine phosphorylation of IR by the Fyn kinase and enhances IR recruitment of P85 and downstream signaling. Third, pretreatment for 15 min with saturated fatty acids suppresses CD36-Fyn enhancement of IR phosphorylation, whereas unsaturated fatty acids are neutral or stimulatory. These findings define mechanisms important for muscle glucose metabolism and optimal insulin responsiveness. Potential human relevance is suggested by genome-wide analysis and RNA sequencing data that associate genetically determined low muscle CD36 expression to incidence of type 2 diabetes.
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http://dx.doi.org/10.2337/db17-1226DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6014550PMC
July 2018

Metabolically normal obese people are protected from adverse effects following weight gain.

J Clin Invest 2015 Feb 2;125(2):787-95. Epub 2015 Jan 2.

BACKGROUND. Obesity is associated with insulin resistance and increased intrahepatic triglyceride (IHTG) content, both of which are key risk factors for diabetes and cardiovascular disease. However, a subset of obese people does not develop these metabolic complications. Here, we tested the hypothesis that people defined by IHTG content and insulin sensitivity as "metabolically normal obese" (MNO), but not those defined as "metabolically abnormal obese" (MAO), are protected from the adverse metabolic effects of weight gain. METHODS. Body composition, multiorgan insulin sensitivity, VLDL apolipoprotein B100 (apoB100) kinetics, and global transcriptional profile in adipose tissue were evaluated before and after moderate (~6%) weight gain in MNO (n = 12) and MAO (n = 8) subjects with a mean BMI of 36 ± 4 kg/m2 who were matched for BMI and fat mass. RESULTS. Although the increase in body weight and fat mass was the same in both groups, hepatic, skeletal muscle, and adipose tissue insulin sensitivity deteriorated, and VLDL apoB100 concentrations and secretion rates increased in MAO, but not MNO, subjects. Moreover, biological pathways and genes associated with adipose tissue lipogenesis increased in MNO, but not MAO, subjects. CONCLUSIONS. These data demonstrate that MNO people are resistant, whereas MAO people are predisposed, to the adverse metabolic effects of moderate weight gain and that increased adipose tissue capacity for lipogenesis might help protect MNO people from weight gain-induced metabolic dysfunction. TRIAL REGISTRATION. ClinicalTrials.gov NCT01184170. FUNDING. This work was supported by NIH grants UL1 RR024992 (Clinical Translational Science Award), DK 56341 (Nutrition and Obesity Research Center), DK 37948 and DK 20579 (Diabetes Center Grant), and UL1 TR000450 (KL2 Award); a Central Society for Clinical and Translational Research Early Career Development Award; and by grants from the Longer Life Foundation and the Kilo Foundation.
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http://dx.doi.org/10.1172/JCI78425DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4319438PMC
February 2015

Regulation of AMPK activation by CD36 links fatty acid uptake to β-oxidation.

Diabetes 2015 Feb 25;64(2):353-9. Epub 2014 Aug 25.

Department of Medicine, Center for Human Nutrition, Washington University School of Medicine in St. Louis, St. Louis, MO Department of Cell Biology & Physiology, Washington University School of Medicine in St. Louis, St. Louis, MO

Increases in muscle energy needs activate AMPK and induce sarcolemmal recruitment of the fatty acid (FA) translocase CD36. The resulting rises in FA uptake and FA oxidation are tightly correlated, suggesting coordinated regulation. We explored the possibility that membrane CD36 signaling might influence AMPK activation. We show, using several cell types, including myocytes, that CD36 expression suppresses AMPK, keeping it quiescent, while it mediates AMPK activation by FA. These dual effects reflect the presence of CD36 in a protein complex with the AMPK kinase LKB1 (liver kinase B1) and the src kinase Fyn. This complex promotes Fyn phosphorylation of LKB1 and its nuclear sequestration, hindering LKB1 activation of AMPK. FA interaction with CD36 dissociates Fyn from the protein complex, allowing LKB1 to remain cytosolic and activate AMPK. Consistent with this, CD36(-/-) mice have constitutively active muscle and heart AMPK and enhanced FA oxidation of endogenous triglyceride stores. The molecular mechanism described, whereby CD36 suppresses AMPK, with FA binding to CD36 releasing this suppression, couples AMPK activation to FA availability and would be important for the maintenance of cellular FA homeostasis. Its dysfunction might contribute to the reported association of CD36 variants with metabolic complications of obesity in humans.
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http://dx.doi.org/10.2337/db14-0582DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4303974PMC
February 2015

Ubiquitination and degradation of the hominoid-specific oncoprotein TBC1D3 is regulated by protein palmitoylation.

Biochem Biophys Res Commun 2013 May 8;434(2):388-93. Epub 2013 Apr 8.

Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO 63110, USA.

Expression of the hominoid-specific oncoprotein TBC1D3 promotes enhanced cell growth and proliferation by increased activation of signal transduction through several growth factors. Recently we documented the role of CUL7 E3 ligase in growth factors-induced ubiquitination and degradation of TBC1D3. Here we expanded our study to discover additional molecular mechanisms that control TBC1D3 protein turnover. We report that TBC1D3 is palmitoylated on two cysteine residues: 318 and 325. The expression of double palmitoylation mutant TBC1D3:C318/325S resulted in protein mislocalization and enhanced growth factors-induced TBC1D3 degradation. Moreover, ubiquitination of TBC1D3 via CUL7 E3 ligase complex was increased by mutating the palmitoylation sites, suggesting that depalmitoylation of TBC1D3 makes the protein more available for ubiquitination and degradation. The results reported here provide novel insights into the molecular mechanisms that govern TBC1D3 protein degradation. Dysregulation of these mechanisms in vivo could potentially result in aberrant TBC1D3 expression and promote oncogenesis.
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http://dx.doi.org/10.1016/j.bbrc.2013.04.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3646999PMC
May 2013

Ubiquitination and degradation of the hominoid-specific oncoprotein TBC1D3 is mediated by CUL7 E3 ligase.

PLoS One 2012 27;7(9):e46485. Epub 2012 Sep 27.

Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Missouri, United States of America.

Expression of the hominoid-specific TBC1D3 oncoprotein enhances growth factor receptor signaling and subsequently promotes cellular proliferation and survival. Here we report that TBC1D3 is degraded in response to growth factor signaling, suggesting that TBC1D3 expression is regulated by a growth factor-driven negative feedback loop. To gain a better understanding of how TBC1D3 is regulated, we studied the effects of growth factor receptor signaling on TBC1D3 post-translational processing and turnover. Using a yeast two-hybrid screen, we identified CUL7, the scaffolding subunit of the CUL7 E3 ligase complex, as a TBC1D3-interacting protein. We show that CUL7 E3 ligase ubiquitinates TBC1D3 in response to serum stimulation. Moreover, TBC1D3 recruits F-box 8 (Fbw8), the substrate recognition domain of CUL7 E3 ligase, in pull-down experiments and in an in vitro assay. Importantly, alkaline phosphatase treatment of TBC1D3 suppresses its ability to recruit Fbw8, indicating that TBC1D3 phosphorylation is critical for its ubiquitination and degradation. We conclude that serum- and growth factor-stimulated TBC1D3 ubiquitination and degradation are regulated by its interaction with CUL7-Fbw8.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0046485PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3459922PMC
February 2013

Structure-function of CD36 and importance of fatty acid signal transduction in fat metabolism.

Annu Rev Nutr 2014 16;34:281-303. Epub 2014 May 16.

Department of Medicine, Center for Human Nutrition, and.

CD36 (cluster of differentiation 36) is a scavenger receptor that functions in high-affinity tissue uptake of long-chain fatty acids (FAs) and contributes under excessive fat supply to lipid accumulation and metabolic dysfunction. This review describes recent evidence regarding the CD36 FA binding site and a potential mechanism for FA transfer. It also presents the view that CD36 and FA signaling coordinate fat utilization, a view that is based on newly identified CD36 actions that involve oral fat perception, intestinal fat absorption, secretion of the peptides cholecystokinin and secretin, regulation of hepatic lipoprotein output, activation of beta oxidation by muscle, and regulation of the production of the FA-derived bioactive eicosanoids. Thus abnormalities of fat metabolism and the associated pathology might involve dysfunction of CD36-mediated signal transduction in addition to the changes in FA uptake.
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http://dx.doi.org/10.1146/annurev-nutr-071812-161220DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4329921PMC
March 2015

CD36 level and trafficking are determinants of lipolysis in adipocytes.

FASEB J 2012 Nov 19;26(11):4733-42. Epub 2012 Jul 19.

Department of Internal Medicine, Center for Human Nutrition, Washington University School of Medicine, St. Louis, MO 63110, USA.

CD36 has been linked to the etiology of insulin resistance and inflammation. We explored its function in regulating adipose tissue lipolysis, which influences fat accumulation by liver and muscle and overall metabolism. Knockdown of CD36 in differentiated 3T3-L1 adipocytes decreased lipolysis in response to 10 μM of the β-adrenergic agonist isoproterenol (by 42%), 10 μM of the adenyl cyclase activator forskolin (by 32%), and 500 μM of the phosphodiesterase (PDE) inhibitor isobutylmethylxanthine (by 33%). All three treatments in the knockdown adipocytes were associated with significant decreases of cAMP levels and of the hormone-sensitive lipase (HSL) and perilipin phosphorylation. An important role for PDE was supported by the lack of inhibition of the lipolysis induced by the poorly hydrolyzable dibutyryl cAMP analog. An additional contributory mechanism was diminished activation of the Src-ERK1/2 pathway. Regulation of lipolysis and lipolytic signaling by CD36 was reproduced with adipose tissue from CD36(-/-) mice. The importance of surface CD36 in this regulation was suggested by the finding that the plasma membrane-impermeable CD36 inhibitor sulfo-N-succinimidyl oleate (20 μM) decreased lipolysis. Interestingly, isoproterenol induced CD36 internalization, and this process was blocked by HSL inhibition, suggesting feedback regulation of adipocyte lipolysis via CD36 trafficking.
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http://dx.doi.org/10.1096/fj.12-206862DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3475246PMC
November 2012

TBC1D3, a hominoid-specific gene, delays IRS-1 degradation and promotes insulin signaling by modulating p70 S6 kinase activity.

PLoS One 2012 13;7(2):e31225. Epub 2012 Feb 13.

Department of Cell Biology and Physiology, [corrected] Washington University School of Medicine, St Louis, Missouri, United States of America.

Insulin/IGF-1 signaling plays a pivotal role in the regulation of cellular homeostasis through its control of glucose metabolism as well as due to its effects on cell proliferation. Aberrant regulation of insulin signaling has been repeatedly implicated in uncontrolled cell growth and malignant transformations. TBC1D3 is a hominoid specific gene previously identified as an oncogene in breast and prostate cancers. Our efforts to identify the molecular mechanisms of TBC1D3-induced oncogenesis revealed the role of TBC1D3 in insulin/IGF-1 signaling pathway. We document here that TBC1D3 intensifies insulin/IGF-1-induced signal transduction through intricate, yet elegant fine-tuning of signaling mechanisms. We show that TBC1D3 expression substantially delayed ubiquitination and degradation of insulin receptor substrate-1 (IRS-1). This effect is achieved through suppression of serine phosphorylation at S636/639, S307 and S312 of IRS-1, which are key phosphorylation sites required for IRS-1 degradation. Furthermore, we report that the effect of TBC1D3 on IRS-1:S636/639 phosphorylation is mediated through TBC1D3-induced activation of protein phosphatase 2A (PP2A), followed by suppression of T389 phosphorylation on p70 S6 kinase (S6K). TBC1D3 specifically interacts with PP2A regulatory subunit B56γ, indicating that TBC1D3 and PP2A B56γ operate jointly to promote S6K:T389 dephosphorylation. These findings suggest that TBC1D3 plays an unanticipated and potentially unique role in the fine-tuning of insulin/IGF-1 signaling, while providing novel insights into the regulation of tumorigenesis by a hominoid-specific protein.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0031225PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3278430PMC
July 2012

Insulin and AMPK regulate FA translocase/CD36 plasma membrane recruitment in cardiomyocytes via Rab GAP AS160 and Rab8a Rab GTPase.

J Lipid Res 2012 Apr 6;53(4):709-17. Epub 2012 Feb 6.

Department of Cell Biology, Washington University School of Medicine, St. Louis, MO 63110, USA.

The FA translocase cluster of differentiation 36 (CD36) facilitates FA uptake by the myocardium, and its surface recruitment in cardiomyocytes is induced by insulin, AMP-dependent protein kinase (AMPK), or contraction. Dysfunction of CD36 trafficking contributes to disordered cardiac FA utilization and promotes progression to disease. The Akt substrate 160 (AS160) Rab GTPase-activating protein (GAP) is a key regulator of vesicular trafficking, and its activity is modulated via phosphorylation. Our study documents that AS160 mediates insulin or AMPK-stimulated surface translocation of CD36 in cardiomyocytes. Knock-down of AS160 redistributes CD36 to the surface and abrogates its translocation by insulin or the AMPK agonist 5-aminoimidazole-4-carboxamide-1-beta-d-ribofuranoside (AICAR). Conversely, overexpression of a phosphorylation-deficient AS160 mutant (AS160 4P) suppresses the stimulated membrane recruitment of CD36. The AS160 substrate Rab8a GTPase is shown via overexpression and knock-down studies to be specifically involved in insulin/AICAR-induced CD36 membrane recruitment. Our findings directly demonstrate AS160 regulation of CD36 trafficking. In myocytes, the AS160 pathway also mediates the effect of insulin, AMPK, or contraction on surface recruitment of the glucose transporter GLUT4. Thus, AS160 constitutes a point of convergence for coordinating physiological regulation of CD36 and GLUT4 membrane recruitment.
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http://dx.doi.org/10.1194/jlr.M023424DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3307647PMC
April 2012

Gating of the mitochondrial permeability transition pore by long chain fatty acyl analogs in vivo.

J Biol Chem 2010 Mar 26;285(10):6879-90. Epub 2009 Dec 26.

Department of Human Nutrition and Metabolism, Hebrew University Medical School, Jerusalem 91120, Israel.

The role played by long chain fatty acids (LCFA) in promoting energy expenditure is confounded by their dual function as substrates for oxidation and as putative classic uncouplers of mitochondrial oxidative phosphorylation. LCFA analogs of the MEDICA (MEthyl-substituted DICarboxylic Acids) series are neither esterified into lipids nor beta-oxidized and may thus simulate the uncoupling activity of natural LCFA in vivo, independently of their substrate role. Treatment of rats or cell lines with MEDICA analogs results in low conductance gating of the mitochondrial permeability transition pore (PTP), with 10-40% decrease in the inner mitochondrial membrane potential. PTP gating by MEDICA analogs is accounted for by inhibition of Raf1 expression and kinase activity, resulting in suppression of the MAPK/RSK1 and the adenylate cyclase/PKA transduction pathways. Suppression of RSK1 and PKA results in a decrease in phosphorylation of their respective downstream targets, Bad(Ser-112) and Bad(Ser-155). Decrease in Bad(Ser-112, Ser-155) phosphorylation results in increased binding of Bad to mitochondrial Bcl2 with concomitant displacement of Bax, followed by PTP gating induced by free mitochondrial Bax. Low conductance PTP gating by LCFA/MEDICA may account for their thyromimetic calorigenic activity in vivo.
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http://dx.doi.org/10.1074/jbc.M109.080416DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2844138PMC
March 2010
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