It has long been hypothesized that abnormalities in lipid biology contribute to degenerative brain diseases. Consistent with this, emerging epidemiologic evidence links lipid alterations with Parkinson disease (PD), and disruption of lipid metabolism has been found to predispose to α-synuclein toxicity. We therefore investigated whether Parkin, an E3 ubiquitin ligase found to be defective in patients with early onset PD, regulates systemic lipid metabolism. We perturbed lipid levels by exposing Parkin+/+ and Parkin–/– mice to a high-fat and -cholesterol diet (HFD). Parkin–/– mice resisted weight gain, steatohepatitis, and insulin resistance. In wild-type mice, the HFD markedly increased hepatic Parkin levels in parallel with lipid transport proteins, including CD36, Sr-B1, and FABP. These lipid transport proteins were not induced in Parkin–/– mice. The role of Parkin in fat uptake was confirmed by increased oleate accumulation in hepatocytes overexpressing Parkin and decreased uptake in Parkin–/– mouse embryonic fibroblasts and patient cells harboring complex heterozygous mutations in the Parkin-encoding gene PARK2. Parkin conferred this effect, in part, via ubiquitin-mediated stabilization of the lipid transporter CD36. Reconstitution of Parkin restored hepatic fat uptake and CD36 levels in Parkin–/– mice, and Parkin augmented fat accumulation during adipocyte differentiation. These results demonstrate that Parkin is regulated in a lipid-dependent manner and modulates systemic fat uptake via ubiquitin ligase–dependent effects. Whether this metabolic regulation contributes to premature Parkinsonism warrants investigation.
Kye-Young Kim, Mark V. Stevens, M. Hasina Akter, Sarah E. Rusk, Robert J. Huang, Alexandra Cohen, Audrey Noguchi, Danielle Springer, Alexander V. Bocharov, Tomas L. Eggerman, Der-Fen Suen, Richard J. Youle, Marcelo Amar, Alan T. Remaley, Michael N. Sack
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Cellular and Molecular Life Sciences | 2021 |
Managing risky assets – mitophagy in vivo
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CD36 Signal Transduction in Metabolic Diseases: Novel Insights and Therapeutic Targeting
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Cells | 2021 |
A Selective Look at Autophagy in Pancreatic β-Cells
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International journal of molecular sciences | 2021 |
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Identification of bioactive metabolites in human iPSC-derived dopaminergic neurons with PARK2 mutation: Altered mitochondrial and energy metabolism
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International journal of molecular sciences | 2021 |
Role and Mechanisms of Mitophagy in Liver Diseases
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Cells | 2020 |
Liver-specific Prkn knockout mice are more susceptible to diet-induced hepatic steatosis and insulin resistance
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Molecular Metabolism | 2020 |
The Role of CD36 in Type 2 Diabetes Mellitus: β-Cell Dysfunction and Beyond
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Diabetes & Metabolism Journal | 2020 |
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Scientific Reports | 2020 |
Molecular Mechanisms And Clinical Implications Of Multiple Forms Of Mitophagy In The Heart
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Frontiers in Cardiovascular Medicine | 2020 |
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Acta Neuropathologica Communications | 2020 |
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Scientific Reports | 2020 |
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Scientific Reports | 2020 |
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The Role of Lipids in Parkinson’s Disease
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The Journal of biological chemistry | 2019 |
Lipidomic Alterations in the Mitochondria of Aged Parkin Null Mice Relevant to Autophagy
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Frontiers in neuroscience | 2019 |
Parkin deficiency prevents chronic ethanol-induced hepatic lipid accumulation through β-catenin accumulation
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Cell Communication and Signaling | 2019 |
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LPS Inhibits Fatty Acid Absorption in Enterocytes through TNF-α Secreted by Macrophages
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Cells | 2019 |
Mechanisms of PINK1, ubiquitin and Parkin interactions in mitochondrial quality control and beyond
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Cellular and Molecular Life Sciences | 2019 |
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American journal of physiology. Endocrinology and metabolism | 2018 |
Parkin in Parkinson’s Disease and Cancer: a Double-Edged Sword
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Molecular Neurobiology | 2018 |
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Science signaling | 2018 |
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Lipids in Health and Disease | 2018 |
Characterization of Dopaminergic System in the Striatum of Young Adult Park2−/− Knockout Rats
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Scientific Reports | 2018 |
Parkin targets NOD2 to regulate astrocyte endoplasmic reticulum stress and inflammation
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Glia | 2018 |
Mitophagy and Mitochondrial Quality Control Mechanisms in the Heart
RA Gottlieb, A Thomas |
Current Pathobiology Reports | 2017 |
Target acquired: Selective autophagy in cardiometabolic disease
TD Evans, I Sergin, X Zhang, B Razani |
Science signaling | 2017 |
CD36 in chronic kidney disease: novel insights and therapeutic opportunities
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Nature Reviews Nephrology | 2017 |
A Rab5 endosomal pathway mediates Parkin-dependent mitochondrial clearance
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Nature Communications | 2017 |
DJ-1 maintains energy and glucose homeostasis by regulating the function of brown adipose tissue
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Cell Discovery | 2017 |
Expanding perspectives on the significance of mitophagy in cancer
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Seminars in Cancer Biology | 2017 |
Parkin targets HIF-1α for ubiquitination and degradation to inhibit breast tumor progression
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Nature Communications | 2017 |
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Parkin-mediated mitophagy is downregulated in browning of white adipose tissue: Parkin Downregulation in White Adipose Browning
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PINK1/Parkin-Dependent Mitochondrial Surveillance: From Pleiotropy to Parkinson's Disease
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Frontiers in molecular neuroscience | 2017 |
Parkin regulation of CHOP modulates susceptibility to cardiac endoplasmic reticulum stress
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Scientific Reports | 2017 |
Beyond Mitophagy: The Diversity and Complexity of Parkin Function
SE Shires, RN Kitsis, ÅB Gustafsson |
Circulation research | 2017 |
Lack of Parkin anticipates the phenotype and affects mitochondrial morphology and mtDNA levels in a mouse model of Parkinson's Disease
M Pinto, N Nissanka, CT Moraes |
The Journal of neuroscience : the official journal of the Society for Neuroscience | 2017 |
Mfge8 regulates enterocyte lipid storage by promoting enterocyte triglyceride hydrolase activity
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DK Costa, BR Huckestein, LR Edmunds, MC Petersen, A Nasiri, GM Butrico, A Abulizi, DB Harmon, C Lu, BS Mantell, DJ Hartman, JP Camporez, RM O'Doherty, GW Cline, GI Shulman, MJ Jurczak |
American journal of physiology. Endocrinology and metabolism | 2016 |
Mitochondrial Function, Biology, and Role in Disease: A Scientific Statement From the American Heart Association
E Murphy, H Ardehali, RS Balaban, F DiLisa, GW Dorn, RN Kitsis, K Otsu, P Ping, R Rizzuto, MN Sack, D Wallace, RJ Youle |
Circulation research | 2016 |
Hepatocellular carcinoma mouse models: Hepatitis B virus-associated hepatocarcinogenesis and haploinsufficient tumor suppressor genes
YC Teng |
World journal of gastroenterology : WJG | 2016 |
Parkin and mitophagy in cancer
JP Bernardini, M Lazarou, G Dewson |
Oncogene | 2016 |
Mitochondrial control of cell bioenergetics in Parkinson’s disease
R Requejo-Aguilar, JP Bolaños |
Free radical biology & medicine | 2016 |
Mitochondrial autophagy in cardiomyopathy
M Tong, J Sadoshima |
Current Opinion in Genetics & Development | 2016 |
Rescue of mitochondrial function in parkin-mutant fibroblasts using drug loaded PMPC-PDPA polymersomes and tubular polymersomes
G Yealland, G Battaglia, O Bandmann, H Mortiboys |
Neuroscience Letters | 2016 |
Association of a PARK2 Germline Variant and Epithelial Ovarian Cancer in a Southern Brazilian Population
PF Klimczak, DH Ventury, FR Faucz, N Settas, CM de Souza, VS Sotomaior |
Oncology | 2016 |
Parkin-mediated mitophagy directs perinatal cardiac metabolic maturation in mice
G Gong, M Song, G Csordas, DP Kelly, SJ Matkovich, GW Dorn |
Science | 2015 |
Glycogen synthase kinase-3-mediated phosphorylation of serine 73 targets sterol response element binding protein-1c (SREBP-1c) for proteasomal degradation
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Bioscience Reports | 2015 |
Mitophagy and cancer
AH Chourasia, ML Boland, KF Macleod |
Cancer & Metabolism | 2015 |
HIF-driven SF3B1 induces KHK-C to enforce fructolysis and heart disease
P Mirtschink, J Krishnan, F Grimm, A Sarre, M Hörl, M Kayikci, N Fankhauser, Y Christinat, C Cortijo, O Feehan, A Vukolic, S Sossalla, SN Stehr, J Ule, N Zamboni, T Pedrazzini, W Krek |
Nature | 2015 |
Molecular Mechanisms of Mitochondrial Autophagy/Mitophagy in the Heart
T Saito, J Sadoshima |
Circulation research | 2015 |
Chemogenomic Profiling of Endogenous PARK2 Expression Using a Genome-Edited Coincidence Reporter
SA Hasson, AI Fogel, C Wang, R MacArthur, R Guha, S Heman-Ackah, S Martin, RJ Youle, J Inglese |
ACS chemical biology | 2015 |
Folic Acid Supplementation Ameliorates Oxidative Stress, Metabolic Functions and Developmental Anomalies in a Novel Fly Model of Parkinson’s Disease
S Srivastav, SK Singh, AK Yadav, S Srikrishna |
Neurochemical Research | 2015 |
Endogenous Parkin Preserves Dopaminergic Substantia Nigral Neurons following Mitochondrial DNA Mutagenic Stress
AM Pickrell, CH Huang, SR Kennedy, A Ordureau, DP Sideris, JG Hoekstra, JW Harper, RJ Youle |
Neuron | 2015 |
PINK1 Is Dispensable for Mitochondrial Recruitment of Parkin and Activation of Mitophagy in Cardiac Myocytes
DA Kubli, MQ Cortez, AG Moyzis, RH Najor, Y Lee, ÅB Gustafsson, J Sadoshima |
PloS one | 2015 |
Convergence of Parkin, PINK1, and α-Synuclein on Stress-induced Mitochondrial Morphological Remodeling
KL Norris, R Hao, LF Chen, CH Lai, M Kapur, PJ Shaughnessy, D Chou, J Yan, JP Taylor, S Engelender, AE West, KL Lim, TP Yao |
The Journal of biological chemistry | 2015 |
A Mechanistic Review of Mitophagy and Its Role in Protection against Alcoholic Liver Disease
J Williams, WX Ding |
Biomolecules | 2015 |
Loss of parkin promotes lipid rafts-dependent endocytosis through accumulating caveolin-1: implications for Parkinson’s disease
SH Cha, YR Choi, CH Heo, SJ Kang, EH Joe, I Jou, HM Kim, SM Park |
Molecular Neurodegeneration | 2015 |
Genome-wide RNAi screen identifies the Parkinson disease GWAS risk locus SREBF1 as a regulator of mitophagy
RM Ivatt, A Sanchez-Martinez, VK Godena, S Brown, E Ziviani, AJ Whitworth |
Proceedings of the National Academy of Sciences | 2014 |
Mfge8 promotes obesity by mediating the uptake of dietary fats and serum fatty acids
A Khalifeh-Soltani, W McKleroy, S Sakuma, YY Cheung, K Tharp, Y Qiu, SM Turner, A Chawla, A Stahl, K Atabai |
Nature Medicine | 2014 |
Regulation of autophagy and mitophagy by nutrient availability and acetylation
BR Webster, I Scott, J Traba, K Han, MN Sack |
Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids | 2014 |
The emerging role of nutrition in Parkinson's disease
SE Seidl, JA Santiago, H Bilyk, JA Potashkin |
Frontiers in aging neuroscience | 2014 |
Inhibition of p53 preserves Parkin-mediated mitophagy and pancreatic -cell function in diabetes
A Hoshino, M Ariyoshi, Y Okawa, S Kaimoto, M Uchihashi, K Fukai, E Iwai-Kanai, K Ikeda, T Ueyama, T Ogata, S Matoba |
Proceedings of the National Academy of Sciences | 2014 |
Parkin Mutations Reduce the Complexity of Neuronal Processes in iPSC-Derived Human Neurons: Parkin Maintains Complexity of Neuronal Processes
Y Ren, H Jiang, Z Hu, K Fan, J Wang, S Janoschka, X Wang, S Ge, J Feng |
Stem Cells | 2014 |
Inhibition of Neuronal Cell Mitochondrial Complex I with Rotenone Increases Lipid -Oxidation, Supporting Acetyl-Coenzyme A Levels
AJ Worth, SS Basu, NW Snyder, C Mesaros, IA Blair |
The Journal of biological chemistry | 2014 |
Mitochondrial Dysfunction and Decrease in Body Weight of a Transgenic Knock-in Mouse Model for TDP-43
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The Journal of biological chemistry | 2014 |
Increased hepatic CD36 expression with age is associated with enhanced susceptibility to nonalcoholic fatty liver disease.
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Aging | 2014 |
Mitochondrial Dysfunction in Cancer
ML Boland, AH Chourasia, KF Macleod |
Frontiers in Oncology | 2013 |
An emerging role of PARK2 in cancer
L Xu, D Lin, D Yin, HP Koeffler |
Journal of Molecular Medicine | 2013 |
Interplay between adipose tissue and blood vessels in obesity and vascular dysfunction
P Gu, A Xu |
Reviews in Endocrine and Metabolic Disorders | 2013 |
HSP72 is a Mitochondrial Stress Sensor Critical for Parkin Action, Oxidative Metabolism, and Insulin Sensitivity in Skeletal Muscle
BG Drew, V Ribas, JA Le, DC Henstridge, J Phun, Z Zhou, T Soleymani, P Daraei, D Sitz, L Vergnes, J Wanagat, K Reue, MA Febbraio, AL Hevener |
Diabetes | 2013 |
Structure and Function of Parkin, PINK1, and DJ-1, the Three Musketeers of Neuroprotection
JF Trempe, EA Fon |
Frontiers in neurology | 2013 |
Molecular hydrogen attenuates fatty acid uptake and lipid accumulation through downregulating CD36 expression in HepG2 cells
A Iio, M Ito, T Itoh, R Terazawa, Y Fujita, Y Nozawa, I Ohsawa, K Ohno, M Ito |
Medical Gas Research | 2013 |
The ubiquitin ligase parkin mediates resistance to intracellular pathogens
PS Manzanillo, JS Ayres, RO Watson, AC Collins, G Souza, CS Rae, DS Schneider, K Nakamura, MU Shiloh, JS Cox |
Nature | 2013 |
Declines in Drp1 and parkin expression underlie DNA damage-induced changes in mitochondrial length and neuronal death
DB Wang, GA Garden, C Kinoshita, C Wyles, N Babazadeh, B Sopher, Y Kinoshita, RS Morrison |
The Journal of neuroscience : the official journal of the Society for Neuroscience | 2013 |
Mitochondria: In Sickness and in Health
J Nunnari, A Suomalainen |
Cell | 2012 |
Parkin protein deficiency exacerbates cardiac injury and reduces survival following myocardial infarction
DA Kubli, X Zhang, Y Lee, RA Hanna, MN Quinsay, CK Nguyen, R Jimenez, S Petrosyan, AN Murphy, AB Gustafsson |
The Journal of biological chemistry | 2012 |
Ranbp2 haploinsufficiency mediates distinct cellular and biochemical phenotypes in brain and retinal dopaminergic and glia cells elicited by the Parkinsonian neurotoxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)
K Cho, K Searle, M Webb, H Yi, PA Ferreira |
Cellular and Molecular Life Sciences | 2012 |
Parkin in the regulation of fat uptake and mitochondrial biology : emerging links in the pathophysiology of Parkinsonʼs disease
KY Kim, MN Sack |
Current Opinion in Lipidology | 2012 |
Phosphatase and tensin homolog (PTEN)-induced putative kinase 1 (PINK1)-dependent ubiquitination of endogenous Parkin attenuates mitophagy: study in human primary fibroblasts and induced pluripotent stem cell-derived neurons
A Rakovic, K Shurkewitsch, P Seibler, A Grünewald, A Zanon, J Hagenah, D Krainc, C Klein |
The Journal of biological chemistry | 2012 |
Mitochondrial dysfunction in Parkinson's disease: molecular mechanisms and pathophysiological consequences
N Exner, AK Lutz, C Haass, KF Winklhofer |
The EMBO Journal | 2012 |
Mitochondrial Quality Control Mediated by PINK1 and Parkin: Links to Parkinsonism
D Narendra, JE Walker, R Youle |
Cold Spring Harbor perspectives in biology | 2012 |
Integration of cellular bioenergetics with mitochondrial quality control and autophagy
BG Hill, GA Benavides, JR Lancaster, S Ballinger, L Dell'Italia, Z Jianhua, VM Darley-Usmar |
Biological Chemistry | 2012 |
A genome wide association study for backfat thickness in Italian Large White pigs highlights new regions affecting fat deposition including neuronal genes
L Fontanesi, G Schiavo, G Galimberti, DG Calò, E Scotti, PL Martelli, L Buttazzoni, R Casadio, V Russo |
BMC Genomics | 2012 |
Copy number variations associated with obesity-related traits in African Americans: a joint analysis between GENOA and HyperGEN
W Zhao, NE Wineinger, HK Tiwari, TH Mosley, U Broeckel, DK Arnett, SL Kardia, EK Kabagambe, YV Sun |
Obesity | 2012 |
Parkinsonism due to mutations in PINK1, parkin, and DJ-1 and oxidative stress and mitochondrial pathways
MR Cookson |
Cold Spring Harbor Perspectives in Medicine | 2012 |
Parkin reinvents itself to regulate fatty acid metabolism by tagging CD36
Nada Abumrad, Darren Moore |
Journal of Clinical Investigation | 2011 |
Pulmonary surfactant: an immunological perspective
ZC Chroneos, Z Sever-Chroneos, VL Shepherd |
Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology | 2009 |