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

Abstract

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

Increased hepatic lipogenesis in insulin resistance and Type 2 diabetes is associated with AMPK signalling pathway up-regulation in Psammomys obesus

“…Since ACC is inhibited by phosphorylation [33,34], we initially hypothesized that the activity of ACC could be decreased in insulin resistant and diabetic animals. Surprisingly, our findings demonstrated an increased trend of ACC activity in these animal groups, which is in agreement with previous results on JCR:LA-cp rats where ACC activity was elevated in the insulin resistance state [35]. The increased activity may be mainly explained by the high ACC protein levels, indicative of sustained transcription process.…”

Adenosine monophosphate-activated protein kinase and nitric oxide in rat steatotic liver transplantation

“…Liver tissue was homogenized as previously described [29][30][31] and proteins were separated by SDS-PAGE and transferred to PVDF membranes. Membranes were immunobloted with antibodies antiphospho-AMPK (Thr172) (1:1000) and anti-AMPK (1:1000) (Cell Signalling, Beverly, MA), anti-eNOS (1:500) and anti-i-iNOS (1:1000) (Transduction Laboratories, Lexington.…”

ATP-Citrate Lyase Reduction Mediates Palmitate-induced Apoptosis in Pancreatic Beta Cells

“…5B). Because palmitate provoked a reduction in total ACLY protein and activity, we tested whether treatment with two structurally unrelated small molecule inhibitors of ACLY, SB-204990 (35) and Medica 16 (37), would be sufficient to cause beta cell apoptosis and ER stress. Indeed, blocking ACLY activity with either inhibitor caused robust beta cell apoptosis (Fig.…”