MEDICA 16 Inhibits Hepatic Acetyl-CoA Carboxylase and Reduces Plasma Triacylglycerol Levels in Insulin-Resistant JCR
| Autor: | James C. Russell, Sandra E. Kelly, Jacob Bar-Tana, Gary D. Lopaschuk, Laura L. Atkinson |
|---|---|
| Rok vydání: | 2002 |
| Předmět: |
medicine.medical_specialty
Endocrinology Diabetes and Metabolism medicine.medical_treatment Hyperlipidemias Palmitic Acids AMP-Activated Protein Kinases Protein Serine-Threonine Kinases Rats Mutant Strains Insulin resistance AMP-activated protein kinase Multienzyme Complexes Hyperinsulinism Internal medicine Internal Medicine medicine Animals Obesity Muscle Skeletal Protein kinase A Beta oxidation Triglycerides Hypolipidemic Agents biology Insulin Acetyl-CoA carboxylase AMPK Skeletal muscle medicine.disease Rats Endocrinology medicine.anatomical_structure Liver biology.protein Insulin Resistance Acetyl-CoA Carboxylase |
| Zdroj: | Diabetes. 51:1548-1555 |
| ISSN: | 1939-327X 0012-1797 |
| DOI: | 10.2337/diabetes.51.5.1548 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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