title: Activation of AMP-activated protein kinase prevents lipotoxicity in retinal pericytes.
abstract: OBJECTIVE
  The recent FIELD study demonstrated that the lipid-lowering agent fenofibrate significantly reduces the development and progression of diabetic retinopathy (DR). These results suggest that lipids may play a causal role in DR. They also suggest that AMP-activated protein kinase (AMPK) activation could account for these findings given that fenofibrate is an AMPK activator. The authors previously demonstrated that free fatty acids, in addition to hyperglycemia, can induce apoptosis in retinal pericytes (PCs), the first cells lost in the diabetic retina. Incubation with the saturated fatty acid palmitate, but not the monounsaturated fatty acid oleate, elicited cytotoxicity in a manner dependent on oxidative stress, NF-κB activation, and ceramide accumulation. In this study, the authors explored whether AMPK can downregulate these pathways and, in doing so, protect PCs from apoptosis.
  
  
  METHODS
  PCs were incubated with palmitate or oleate to determine whether the factors previously linked to lipotoxicity were uniquely increased by palmitate. The effects of AMPK activation on these parameters and on apoptosis were concurrently examined.
  
  
  RESULTS
  Only palmitate increased NF-κB activation, ceramide and diacylglycerol mass, and apoptosis. Activation of AMPK with AICAR or, where used, expression of a constitutively active AMPK prevented all these effects. In contrast, both palmitate and oleate markedly increased oxidative stress, and the activation of AMPK did not prevent this.
  
  
  CONCLUSIONS
  AMPK activation prevents the metabolic abnormalities and apoptosis specifically caused by palmitate in cultured PCs. Pharmacologic agents that activate AMPK in the diabetic retina may warrant consideration as a therapeutic option to avert PC apoptosis and to maintain microvascular homeostasis.
authors.affiliation: Diabetes and Metabolism Research Unit, Department of Medicine and Section of Endocrinology, Boston University School of Medicine, Boston, Massachusetts 02118, USA.
authors.forename: José M
authors.initials: JM
authors.lastname: Cacicedo
authors.forename: Sunun
authors.initials: S
authors.lastname: Benjachareonwong
authors.forename: Eva
authors.initials: E
authors.lastname: Chou
authors.forename: Norito
authors.initials: N
authors.lastname: Yagihashi
authors.forename: Neil B
authors.initials: NB
authors.lastname: Ruderman
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Ido
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D000108:Acetylcarnitine / Q000494:pharmacology; D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002417:Cattle; D002478:Cells, Cultured; D019610:Cytoprotection; D004075:Diglycerides / Q000378:metabolism; D004578:Electron Spin Resonance Spectroscopy; D004789:Enzyme Activation; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology; D020287:In Situ Nick-End Labeling; D016328:NF-kappa B / Q000378:metabolism; D019301:Oleic Acid / Q000633:toxicity*; D018384:Oxidative Stress / Q000187:drug effects; D010168:Palmitates / Q000633:toxicity*; D020286:Pericytes / Q000187:drug effects* / Q000201:enzymology; D012171:Retinal Vessels / Q000166:cytology*; D013107:Sphingolipids / Q000378:metabolism
chemical_list: D004075:Diglycerides; D016328:NF-kappa B; D010168:Palmitates; D013107:Sphingolipids; D019301:Oleic Acid; D000108:Acetylcarnitine; D055372:AMP-Activated Protein Kinases