AMPK activation by long chain fatty acyl analogs

196

153

This article is available online at http://www.jlr.org Cardiovascular disease (CVD) remains a leading cause of morbidity and mortality in the Western world ( 1 ). Elevated levels of LDL-cholesterol (LDL-C) have consistently shown a positive association with the development of CVD, justifying the current therapeutic strategies to prevent CVD primarily by the use of statins. Members of this drug class inhibit HMG-CoA reductase (HMGR), the rate-limiting enzyme for de novo cholesterol synthesis, thereby leading to decreased LDL-C ( 2-4 ). While the benefi ts of statins have been documented ( 2 ), many individuals on statin therapy still remain at a higher risk of developing CVD. It is possible this residual risk is a result of other metabolic syndrome (MetS) risk factors characterized by dyslipidemia and insulin resistance and is also in part due to statin intolerance ( 5-7 ) and noncompliance often related to statininduced myalgia ( 8, 9 ). Statins are effective at decreasing LDL-C and CVD; however, frequent muscle-related side effects limit dosage and impede maximal risk reduction in dyslipidemic patients ( 10 ). Furthermore, recent evidence suggests that high-dose statins may increase the risk of developing type 2 diabetes (T2D) ( 11 ), further justifying the need for alternative therapeutic interventions that have statin-like effects for lowering LDL-C and are designed to Abstract ETC-1002 (8-hydroxy-2,2,14,14-tetramethylpentadecanedioic acid) is a novel investigational drug being developed for the treatment of dyslipidemia and other cardio-metabolic risk factors. The hypolipidemic, anti-atherosclerotic, anti-obesity, and glucose-lowering properties of ETC-1002, characterized in preclinical disease models, are believed to be due to dual inhibition of sterol and fatty acid synthesis and enhanced mitochondrial long-chain fatty acid ␤ -oxidation. However, the molecular mechanism(s) mediating these activities remained undefi ned.

Section: Discussionmentioning

confidence: 87%

AMP-activated protein kinase and ATP-citrate lyase are two distinct molecular targets for ETC-1002, a novel small molecule regulator of lipid and carbohydrate metabolism

Pinkosky

Filippov

Srivastava

et al. 2013

196

153

“…7 ), which are not metabolized beyond their acyl-CoA thioesters, inhibit lipid synthesis ( 278 ) and show hypolipidemic and antidiabetogenic activities ( 279 ). In a more recent study ( 280 ), MEDICA analogs are shown to activate recombinant AMPK in a cell-free system, in cell lines such as HepG2 and 3T3-L1 and in diabetic db/db mice. Activation of AMPK in the latter animal model normalized blood glucose and suppressed hepatic glucose production.…”

Section: Long Chain-fatty Acids Pufa and Fatty Acid Analogsmentioning

confidence: 99%

AMP-activated protein kinase: an emerging drug target to regulate imbalances in lipid and carbohydrate metabolism to treat cardio-metabolic diseases

Srivastava

Pinkosky

Filippov

et al. 2012

254

179

This article is available online at http://www.jlr.org termed as metabolic syndrome (MetS) ( 1 ), characterized by a clustering of major risk factors for developing cardiovascular disease. Obesity, representing derangement in energy balances, is tightly linked with the development of type-2 diabetes through its ability to engender insulin resistance, leading to glucose intolerance and development of type-2 diabetes and dyslipidemia. Thus, insulin resistance The pathophysiology of diabetes and obesity is a very complex process involving many pathways. Deregulation of these pathways gives rise to metabolic abnormalities

“…MEDICA analogs (8)(9)(10)(11)(12) consist of long-chain methylsubstituted ␣ , -dicarboxylic acids [e.g., HOOC-CH 2 -C( ␤ )(CH 3 ) 2 -(CH 2 ) 10 -C( ␤ )(CH 3 ) 2 -CH 2 -COOH defi ned as MEDICA16/M ␤ ␤ ]. MEDICA analogs are not esterifi ed into lipids, and the methyl substitutions at the ␤ , ␤ ' positions block their ␤ -oxidation.…”

Section: Western Blot Analysismentioning

confidence: 99%

“…Hence, MEDICA analogs may simulate LCFA effects in the lipolysis context while avoiding its own esterifi cation into adipose fat. Indeed, treatment of animal models of diabesity (e.g., Zucker, cp/cp, db/db, ob/ob) with MEDICA analogs has been reported to result in pronounced decrease in plasma FFA, hepatic glucose and lipoprotein production, with concomitant increase in total body glucose uptake and plasma lipoprotein clearance (9)(10)(11)(12). In fact, the overall phenotype of MEDICA-treated animal models of diabesity appears to be essentially similar to that of HSL-knockouts ( 14 ), indicating that inhibition of agonist-induced lipolysis could play a role in total body sensitization to insulin by MEDICA analogs.…”

Section: Western Blot Analysismentioning

confidence: 99%

“…Male Wistar rats weighing 250-275 g and fed standard rodent diet (Teklad 2018) were daily dosed by gavage for fi ve consecutive days with 200 mg M ␤ ␤ /kg body weight in 1% carboxy methyl cellulose (CMC) or with vehicle only, in line with previously reported dose-effi cacy studies (8)(9)(10)(11)(12). Fasting animals were then implanted with PE50 jugular vein cannula under ketamine/xylazine anesthesia and left to recover for 24 h. On the following day, the animals were dosed with M ␤ ␤ or vehicle, followed 120 min later by single intraperitoneal injection of 10 mg isoproterenol/kg body weight.…”

Section: Animalsmentioning

confidence: 99%

See 1 more Smart Citation

Suppression of adipose lipolysis by long-chain fatty acid analogs

Kalderon

Azazmeh

Azulay

et al. 2012

Self Cite

This article is available online at http://www.jlr.org lipoproteins. Agonist-induced lipolysis is mediated by consecutive activation of the adenylate cyclase (AC), resulting in cAMP production and protein kinase A (PKA) activation by cAMP, followed by PKA-induced phosphorylation of hormone-sensitive lipase (HSL) at three serine residues (563, 659, and 660), resulting in its activation and translocation from the cytosol to the lipid-droplet surface. Concomitant with HSL phosphorylation, the phosphorylation of perilipin by PKA at multiple sites (S81, S222, S276, and S517) results in a dynamic restructuring of the lipid-droplet surface, in facilitating the translocation of phosphorylated HSL to the lipid droplet, and in activating its hydrolyzing activity. Perilipin phosphorylation by PKA further results in releasing CGI-58 from the lipid droplet, in its association with adipose triacylglycerol lipase (ATGL), and in activating its lipolytic activity. Activated ATGL, HSL, and monoglyceride lipase may act now consecutively in hydrolyzing adipose triacyglycerols to diacylglycerol, monoacylglycerol, and fi nally to free glycerol and LCFA. Agonist-induced cAMP and lipolysis is restrained by insulin due to cAMP hydrolysis by insulin-activated phosphodiesterase3B (PDE3B) ( 2 ), combined with insulin-induced reesterifi cation of LCFA into adipose fat (reviewed in Ref.3 ). Indeed, increased adipose effl ux of free LCFA, due to increased adipose lipolysis and/or suppression of adipose LCFA reesterifi cation, is considered a cornerstone of diabetes. Agonist-induced lipolysis is further robustly inhibited by the LCFA generated during lipolysis ( 4, 5 ). In fact, agonist-induced lipolysis is made possible only by removing the free nonesterifi ed LCFA product through their binding to medium albumin or by frequent medium replacement Lipolysis of adipose fat stores results in the production of nonesterifi ed long-chain fatty acids (LCFA) in response to changes in energy requirements and availability (reviewed in Ref. 1 ). Fatty acids derived by adipose fat lipolysis may either be reesterifi ed into adipose fat, or serve as major source of oxidizable substrate for muscle activity and as precursor for the hepatic production of triacylglycerol-richFunded by Eurostars project E!5138.