title: Parkin is a lipid-responsive regulator of fat uptake in mice and mutant human cells.
abstract: 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.
authors.affiliation: Center for Molecular Medicine, NHLBI, 10 Center Drive, Bethesda, Maryland, 20892-1454, USA.
authors.forename: Kye-Young
authors.initials: KY
authors.lastname: Kim
authors.forename: Mark V
authors.initials: MV
authors.lastname: Stevens
authors.forename: M Hasina
authors.initials: MH
authors.lastname: Akter
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Rusk
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Huang
authors.forename: Alexandra
authors.initials: A
authors.lastname: Cohen
authors.forename: Audrey
authors.initials: A
authors.lastname: Noguchi
authors.forename: Danielle
authors.initials: D
authors.lastname: Springer
authors.forename: Alexander V
authors.initials: AV
authors.lastname: Bocharov
authors.forename: Tomas L
authors.initials: TL
authors.lastname: Eggerman
authors.forename: Der-Fen
authors.initials: DF
authors.lastname: Suen
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Youle
authors.forename: Marcelo
authors.initials: M
authors.lastname: Amar
authors.forename: Alan T
authors.initials: AT
authors.lastname: Remaley
authors.forename: Michael N
authors.initials: MN
authors.lastname: Sack
mesh_terms: D000273:Adipose Tissue / Q000166:cytology / Q000378:metabolism; D000818:Animals; D001831:Body Temperature; D018955:CD36 Antigens / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D004041:Dietary Fats / Q000378:metabolism*; D004435:Eating; D004734:Energy Metabolism; D005947:Glucose / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance; D050356:Lipid Metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010300:Parkinson Disease / Q000235:genetics / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D015430:Weight Gain; D051844:alpha-Synuclein / Q000378:metabolism
chemical_list: D018955:CD36 Antigens; D004041:Dietary Fats; D007328:Insulin; D051844:alpha-Synuclein; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein; D005947:Glucose