Regulation of Acetyl CoA Carboxylase and Carnitine Palmitoyl Transferase‐1 in Rat Adipocytes

Abstract

. Regulation of acetyl CoA carboxylase and carnitine palmitoyl transferase-1 in rat adipocytes. Obes Res. 2005;13:1530 -1539. Objective: Acetyl CoA carboxylase (ACC) is a key enzyme in energy balance. It controls the synthesis of malonyl-CoA, an allosteric inhibitor of carnitine palmitoyltransferase-1 (CPT-I). CPT-I is the gatekeeper of free fatty acid (FFA) oxidation. To test the hypothesis that both enzymes play critical roles in regulation of FFA partitioning in adipocytes, we compared enzyme mRNA expression and specific activity from fed, fasted, and diabetic rats. Research Methods and Procedures: Direct effects of nutritional state, insulin, and FFAs on CPT-I and ACC mRNA expression were assessed in adipocytes, liver, and cultured adipose tissue explants. We also determined FFA partitioning in adipocytes from donors exposed to different nutritional conditions. Results: CPT-I mRNA and activity decreased in adipocytes but increased in liver in response to fasting. ACC mRNA and activity decreased in both adipocytes and liver during fasting. These changes were not caused directly by fastingassociated changes in plasma insulin and FFA concentrations because insulin suppressed CPT-I mRNA and did not affect ACC mRNA in vitro, whereas exogenous oleate had no effect on either. Despite the decrease in adipocyte CPT-I mRNA and specific activity, CO 2 production from endogenous FFAs increased, suggesting increased FFA transport through CPT-I for ␤-oxidation. Discussion: Stimulation of FFA transport through CPT-I occurs in both tissues, but CPT-I mRNA and specific activity correlate with FFA transport in liver and not in adipocytes. We conclude that the mechanism responsible for increasing FFA oxidation in adipose tissue during fasting involves mainly allosteric regulation, whereas altered gene expression may play a central role in the liver.

Obesity and Insulin Resistance-Related Changes in the Expression of Lipogenic and Lipolytic Genes in Morbidly Obese Subjects

“…The ACC1 gene has an inducible expression in response to a variety of factors, including insulin [23]. Although our results show a negative correlation with plasma insulin levels and the HOMA-IR, the relation between ACC1 and insulin resistance is unclear [22,23], with less extensive studies in adipocytes [24].…”

“…ACC1 is highly expressed in adipose tissue [22] and plays an important role in energy balance by controlling malonyl-CoA synthesis. The ACC1 gene has an inducible expression in response to a variety of factors, including insulin [23].…”

Aldo-keto Reductase Family 1 B10 Affects Fatty Acid Synthesis by Regulating the Stability of Acetyl-CoA Carboxylase-α in Breast Cancer Cells

“…It is the rate-limiting step of de novo fatty acid synthesis (12). In normal tissues, ACCA activity is tightly regulated by both metabolite-mediated allosteric and phospho-dependent regulations.…”

“…During tumorigenic transformation of human mammary epithelial cells (HMEC), AKR1B10 is up-regulated and associates with acetyl-CoA carboxylase-␣ (ACCA). ACCA is a rate-limiting enzyme of de novo synthesis of long chain fatty acids, catalyzing the formation of malonyl-CoA by ATP-dependent carboxylation of acetyl-CoA (11,12). Increased lipogenesis is an important characteristic of cancer cells and likely contributes to the development and progression of cancer, but the regulatory mechanisms remain to be elucidated (13,14).…”

Effects of Metabolic Risk Factors on Production of Plasminogen Activator Inhibitor-1 and Adiponectin by Adipocytes

“…8 Accordingly, exogenous-added triglycerides could transform into FFAs by the lipoprotein lipase (LPL) around the adipocytes and then the generated FFAs are taken into adipocytes, leading to increased PAI-1 production. On the other hand, insulin inhibits carnitine palmitoyl transferase-1 (CPT-1) mRNA in adipocytes 9 and it might suppress -oxidation of FFAs, leading to accumulation of FFAs in adipocytes. In this way, both triglycerides and insulin increase the FFA levels in adipocytes, leading to PAI-1 production through oxidative stress.…”