Synthesis and hypolipidemic and antidiabetogenic activities of .beta.,.beta.,.beta.',.beta.'-tetrasubstituted, long-chain dioic acids

Bar‐Tana, Jacob; S, Ben-Shoshan; Jc, Blum; Migron, Yoelit; Hertz, Rachel; Pill, Johannes; Rose-Khan, G.; Ec, Witte

doi:10.1021/jm00129a010

Cited by 57 publications

(54 citation statements)

References 2 publications

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“…Treatment with MEDICA 16. MEDICA 16 (␤,␤Ј-tetramethyl hexadecanedioic acid) is a long-chain fatty acyl analog developed as a hypolipidemic and antiobesityantidiabetogenic compound (30). Previous studies have demonstrated that MEDICA 16 significantly reduces intracellular TG content in gastrocnemius muscle, and this reduction is accompanied by an increase in insulin sensitivity (29).…”

Section: Resultsmentioning

confidence: 99%

MEDICA 16 Inhibits Hepatic Acetyl-CoA Carboxylase and Reduces Plasma Triacylglycerol Levels in Insulin-Resistant JCR

et al. 2002

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Intracellular triacylglycerol (TG) content of liver and skeletal muscle contributes to insulin resistance, and a significant correlation exists between TG content and the development of insulin resistance. Because acetylCoA carboxylase (ACC) is the rate-limiting enzyme for liver fatty acid biosynthesis and a key regulator of muscle fatty acid oxidation, we examined whether ACC plays a role in the accumulation of intracellular TG. We also determined the potential role of 5-AMP-activated protein kinase (AMPK) in this process, since it can phosphorylate and inhibit ACC activity in both liver and muscle. TG content, ACC, and AMPK were examined in the liver and skeletal muscle of insulin-resistant JCR: LA-cp rats during the time frame when insulin resistance develops. At 12 weeks of age, there was a threefold elevation in liver TG content and a sevenfold elevation in skeletal muscle TG content. Hepatic ACC activity was significantly elevated in 12-week-old JCR: LA-cp rats compared with lean age-matched controls (8.75 ؎ 0.53 vs. 3.30 ؎ 0.18 nmol ⅐ min ؊1 ⅐ mg ؊1 , respectively), even though AMPK activity was also increased. The observed increase in hepatic ACC activity was accompanied by a 300% increase in ACC protein expression. There were no significant differences in ACC activity, ACC protein expression, or AMPK activity in the skeletal muscle of the 12-week JCR:LA-cp rats. Treatment of 12-week JCR:LA-cp rats with MEDICA 16 (an ATP-citrate lyase inhibitor) resulted in a decrease in hepatic ACC and AMPK activities, but had no effect on skeletal muscle ACC and AMPK. Our data suggest that alterations in ACC or AMPK activity in muscle do not contribute to the development of insulin resistance. However, increased liver ACC activity in the JCR:LA-cp rat appears to contribute to the development of lipid abnormalities, although this increase does not appear to occur secondary to a decrease in AMPK activity. Diabetes 51:1548 -1555, 2002

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Section: Resultsmentioning

confidence: 99%

MEDICA 16 Inhibits Hepatic Acetyl-CoA Carboxylase and Reduces Plasma Triacylglycerol Levels in Insulin-Resistant JCR

et al. 2002

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“…ACC, acetyl-CoA carboxylase; ACS, acyl-CoA synthetase; ␤ -Ox, ␤ -oxidation; CPT-1, carnitine palmitoyltransferase-1; G6Pase, glucose 6-phosphatase; HMGR, HMG-CoA reductase; PEPCK, phosphoenolpyruvate carboxykinase; TCA, tricarboxylic acid. compounds (82)(83)(84)(85)(86)(87)(88)(89)(90)(91)(92) and provide further clarity into their respective mechanisms ( 84,91,(93)(94)(95)(96)(97)(98)(99)(100).…”

Section: Discussionmentioning

confidence: 99%

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

Journal of Lipid Research

197

153

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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.

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“…Coenzyme A, palmitoyl-CoA, stearoyl-CoA, linoleoyl-CoA, arachidonoyl-CoA, arachidonic acid, and bezafibrate were from Sigma. Medica 16, as well as the coenzyme A thioesters of Medica 16 and bezafibrate, were chemically synthesized as described (21,22).…”

Section: Methodsmentioning

confidence: 99%

Ligand Specificity and Conformational Dependence of the Hepatic Nuclear Factor-4α (HNF-4α)

Petrescu¹,

Hertz²,

Bar‐Tana³

et al. 2002

Journal of Biological Chemistry

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125

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Hepatic nuclear factor-4␣ (HNF-4␣ Hepatic nuclear factor 4 (HNF-4)1 is a member of the superfamily of nuclear receptors which includes steroid hormone receptors and nonsteroid ligand dependent transcription factors, e.g. thyroid hormone receptor, retinoid X receptor, retinoid acid receptor, and peroxisome proliferator-activated receptors (PPARs) (reviewed in Ref. 1). HNF-4␣ isoforms (␣ 1 -␣ 3 ) have been cloned and characterized and are expressed in mammals in liver, kidney, intestine, and pancreas (reviewed in Ref.2). Unlike retinoid X receptor ␣, with which it has 40% amino acid sequence homology, HNF-4 does not form heterodimers with any other nuclear receptor, but binds to direct repeat-1 DNA sequences as homodimer (3). Direct repeat-1 motifs are promiscuous binding sites for HNF-4, PPAR, retinoid acid receptor, retinoid X receptor, chicken ovalbumin upstream-promoter transcription factor, and chicken ovalbumin upstream-promoter transcription factor homo-or heterodimers (4).HNF-4␣ responsive genes encode transcription factors (HNF-1␣, PXR), proteins involved in fatty acid, lipoprotein, and lipid metabolism (apoA-I, apoA-II, apoB, apoC-II, apoC-III, L p (a), microsomal triglyceride transfer protein, mitochondrial fatty acyl-CoA dehydrogenases, and fatty acid-binding protein), carbohydrate metabolism (insulin, glut2, glucose-6-phosphatase, phosphoenolpyruvate carboxykinase, pyruvate kinase, aldolase B, and glyceraldehyde-3-phosphate dehydrogenase), amino acid and protein metabolism (ornithine transcarbamylase, tyrosine aminotransferase, phenylalanine hydroxylase, and antitrypsin ␣ 1 ), P450 enzymes (steroid 15␣-hydroxylase, fatty acyl -hydroxylase, cholesterol-7␣-hydroxylase, and drug metabolizing P450 enzymes (cyp3␣ 4 -6)), hematopoiesis (erythropoietin and transferrin), blood coagulation (factors VII, IX, and X and fibrinogen), and others (e.g. cellular retinolbinding protein and transthyretin) (reviewed in Refs. 2 and 5-14). Since HNF-4␣ activates the transcription of some nuclear receptors (HNF-1␣) and may further directly interact with other transcription factors (HNF-1␣), the above list of HNF-4␣ responsive genes may include some which are transcriptionally affected by HNF-4␣ indirectly.The first demonstration of putative HNF-4 ligands showed that long chain fatty acyl-CoA (LCFA-CoAs) thioesters (15), as well as CoA-thioesters of hypolipidemic peroxisome prolifera-

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Synthesis and hypolipidemic and antidiabetogenic activities of .beta.,.beta.,.beta.',.beta.'-tetrasubstituted, long-chain dioic acids

Cited by 57 publications

References 2 publications

MEDICA 16 Inhibits Hepatic Acetyl-CoA Carboxylase and Reduces Plasma Triacylglycerol Levels in Insulin-Resistant JCR

MEDICA 16 Inhibits Hepatic Acetyl-CoA Carboxylase and Reduces Plasma Triacylglycerol Levels in Insulin-Resistant JCR

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

Ligand Specificity and Conformational Dependence of the Hepatic Nuclear Factor-4α (HNF-4α)

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