Effects of a novel dual lipid synthesis inhibitor and its potential utility in treating dyslipidemia and metabolic syndrome

Abstract

We have identified a novel -hydroxy-alkanedicarboxylic acid, ESP 55016, that favorably alters serum lipid variables in obese female Zucker (fa/fa) rats. ESP 55016 reduced serum non-HDL-cholesterol (non-HDL-C), triglyceride, and nonesterified fatty acid levels while increasing serum HDL-C and ␤ -hydroxybutyrate levels in a dose-dependent manner. ESP 55016 reduced fasting serum insulin and glucose levels while also suppressing weight gain. In primary rat hepatocytes, ESP 55016 increased the oxidation of

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

“…ETC-1002 has been previously shown to inhibit de novo sterol and fatty acid synthesis in primary rat hepatocytes in vitro and in vivo, with equal potency ( 12 ). In these studies, ETC-1002-CoA thioester was identifi ed as the primary active form of ETC-1002 and was shown to inhibit partially purifi ed ACC (IC 50 = 29 M) without activating the AMPK pathway in vitro ( 12 ).…”

“…In these studies, ETC-1002-CoA thioester was identifi ed as the primary active form of ETC-1002 and was shown to inhibit partially purifi ed ACC (IC 50 = 29 M) without activating the AMPK pathway in vitro ( 12 ). In a follow-up study reported here, we unexpectedly found a marked and sustained increase in AMPK (T172) (358.3% ± 48.14; P = 0.0007) and ACC (S79) phosphorylation (164.7% ± 12.39; P = 0.001) ( Fig.…”

“…ETC-1002 favorably changes lipid profi les in preclinical models of dyslipidemia ( 12 ), benefi ts glucose homeostasis in mouse models of impaired glycemic control ( 12,13 ), and decreases atherosclerosis in LDL-receptor-defi cient mice ( 14 ). Importantly, clinical studies have shown that ETC-1002 reduces LDL-C levels in subjects with mild dyslipidemia and has benefi cial effects on other relevant cardio-metabolic risk factors, including insulin levels, hsCRP, and blood pressure ( 15 ).…”

“…Working solutions of ETC-1002 were prepared in serum-free DMEM containing 12 mM HEPES, 10,000 U/ml penicillin, and 100 g/ml streptomycin. ETC-1002-CoA was synthesized using rat liver microsomes essentially as described by Cramer et al ( 12 ). For in vivo experiments, ETC-1002 dosing solutions were formulated by preparing a disodium salt aqueous solution using 2:1 molar ratio of NaOH to ETC-1002 in water.…”

Lipids, blood pressure and kidney update 2014

“…This drug has beneficial effects on proatherogenic lipids through enhance of the fatty acid oxidation and inhibition of fatty acid and sterol synthesis in experimental models [90,91]. A single-center, double blind, placebocontrolled trial (n = 60 patients) assessed the efficacy and safety of ETC-1002 in patients with type 2 diabetes mellitus [92].…”