title: RLIP76, a glutathione-conjugate transporter, plays a major role in the pathogenesis of metabolic syndrome.
abstract: OBJECTIVE
  Characteristic hypoglycemia, hypotriglyceridemia, hypocholesterolemia, lower body mass, and fat as well as pronounced insulin-sensitivity of RLIP76⁻/⁻ mice suggested to us the possibility that elevation of RLIP76 in response to stress could itself elicit metabolic syndrome (MSy). Indeed, if it were required for MSy, drugs used to treat MSy should have no effect on RLIP76⁻/⁻ mice.
  
  
  METHODS
  Blood glucose (BG) and lipid measurements were performed in RLIP76⁺/⁺ and RLIP76⁻/⁻ mice, using Ascensia Elite Glucometer® for glucose and ID Labs kits for cholesterol and triglycerides assays. The ultimate effectors of gluconeogenesis are the three enzymes: PEPCK, F-1,6-BPase, and G6Pase, and their expression is regulated by PPARγ and AMPK. The activity of these enzymes was tested by protocols standardized by us. Expressions of RLIP76, PPARα, PPARγ, HMGCR, pJNK, pAkt, and AMPK were performed by Western-blot and tissue staining.
  
  
  RESULTS
  The concomitant activation of AMPK and PPARγ by inhibiting transport activity of RLIP76, despite inhibited activity of key glucocorticoid-regulated hepatic gluconeogenic enzymes like PEPCK, G6Pase and F-1,6-BP in RLIP76⁻/⁻ mice, is a salient finding of our studies. The decrease in RLIP76 protein expression by rosiglitazone and metformin is associated with an up-regulation of PPARγ and AMPK.
  
  
  CONCLUSIONS
  All four drugs, rosiglitazone, metformin, gemfibrozil and atorvastatin failed to affect glucose and lipid metabolism in RLIP76⁻/⁻ mice. Studies confirmed a model in which RLIP76 plays a central role in the pathogenesis of MSy and RLIP76 loss causes profound and global alterations of MSy signaling functions. RLIP76 is a novel target for single-molecule therapeutics for metabolic syndrome.
authors.affiliation: Department of Diabetes and Metabolic Diseases Research, Beckman Research Institute, City of Hope, National Medical Center, Duarte, California, United States of America. ssinghal@coh.org
authors.forename: Jyotsana
authors.initials: J
authors.lastname: Singhal
authors.forename: Lokesh
authors.initials: L
authors.lastname: Nagaprashantha
authors.forename: Rit
authors.initials: R
authors.lastname: Vatsyayan
authors.forename: Sanjay
authors.initials: S
authors.lastname: Awasthi
authors.forename: Sharad S
authors.initials: SS
authors.lastname: Singhal
mesh_terms: D000818:Animals; D016375:Antisense Elements (Genetics) / Q000627:therapeutic use; D000069059:Atorvastatin; D020690:GTPase-Activating Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015248:Gemfibrozil / Q000627:therapeutic use; D006538:Heptanoic Acids / Q000627:therapeutic use; D007004:Hypoglycemic Agents / Q000627:therapeutic use; D000960:Hypolipidemic Agents / Q000627:therapeutic use; D024821:Metabolic Syndrome / Q000188:drug therapy / Q000235:genetics / Q000503:physiopathology*; D008687:Metformin / Q000627:therapeutic use; D051379:Mice; D018345:Mice, Knockout; D011758:Pyrroles / Q000627:therapeutic use; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000627:therapeutic use
chemical_list: D016375:Antisense Elements (Genetics); D020690:GTPase-Activating Proteins; D006538:Heptanoic Acids; D007004:Hypoglycemic Agents; D000960:Hypolipidemic Agents; D011758:Pyrroles; C490620:Ralbp1 protein, mouse; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D008687:Metformin; D000069059:Atorvastatin; D015248:Gemfibrozil