We found a match
Your institution may have access to this item. Find your institution then sign in to continue.
- Title
MEDICA 16 inhibits hepatic acetyl-CoA carboxylase and reduces plasma triacylglycerol levels in insulin-resistant JCR: LA-cp rats.
- Authors
Atkinson, Laura L.; Kelly, Sandra E.; Russell, James C.; Bar-Tana, Jacob; Lopaschuk, Gary D.
- 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 acetyl-CoA 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. min(-1). 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.
- Subjects
INSULIN resistance; FATTY acid synthesis; ENZYME inhibitors; DRUG therapy for hyperlipidemia; ENZYME metabolism; ANIMAL experimentation; ANTILIPEMIC agents; COMPARATIVE studies; FATTY acids; HYPERINSULINISM; HYPERLIPIDEMIA; LIVER; RESEARCH methodology; MEDICAL cooperation; OBESITY; PHOSPHOTRANSFERASES; RATS; RESEARCH; TRANSFERASES; TRIGLYCERIDES; EVALUATION research; SKELETAL muscle; PHARMACODYNAMICS
- Publication
Diabetes, 2002, Vol 51, Issue 5, p1548
- ISSN
0012-1797
- Publication type
journal article
- DOI
10.2337/diabetes.51.5.1548