More Direct Evidence for a Malonyl-CoA–Carnitine Palmitoyltransferase I Interaction as a Key Event in Pancreatic β-Cell Signaling

Abstract

We sought to explore the emerging concept that malonyl-CoA generation, with concomitant suppression of mitochondrial carnitine palmitoyltransferase I (CPT I), represents an important component of glucose-stimulated insulin secretion (GSIS) by the pancreatic beta-cell (Prentki M, Vischer S, Glennon MC, Regazzi R, Deeney JT, Corkey BE: Malonyl-CoA and long-chain acyl-CoA esters as metabolic coupling factors in nutrient-induced insulin secretion. J Biol Chem 267:5802-5810, 1992). Accordingly, pancreases from fed rats were perfused with basal (3 mM) followed by high (20 mM) glucose in the absence or presence of 2 mM hydroxycitrate (HC), an inhibitor of ATP-citrate (CIT) lyase (the penultimate step in the glucose-->malonyl-CoA conversion). HC profoundly inhibited GSIS, whereas CIT had no effect. Inclusion of 0.5 mM palmitate in the perfusate significantly enhanced GSIS and completely offset the negative effect of HC. In isolated islets, HC stimulated [1-14C]palmitate oxidation in the presence of basal glucose and markedly obtunded the inhibitory effect of high glucose. Directional changes in 14C incorporation into phospholipids were opposite to those of 14CO2 production. At a concentration of 0.2 mM, 2-bromostearate, 2-bromopalmitate and etomoxir (all CPT I inhibitors) potentiated GSIS by the pancreas and inhibited palmitate oxidation in islets. However, at 0.05 mM, etomoxir did not influence insulin secretion but still caused significant suppression of fatty acid oxidation. The results provide more direct evidence for a pivotal role of malonyl-CoA suppression of CPT I, with attendant elevation of the cytosolic long-chain acyl-CoA concentration, in GSIS from the normal pancreatic beta-cell.(ABSTRACT TRUNCATED AT 250 WORDS)

Glibenclamide inhibits islet carnitine palmitoyltransferase 1 activity, leading to PKC-dependent insulin exocytosis

“…6) and in previous reports from other groups (8,44). Moreover, etomoxir elevates DAG contents (19), adding further credence to our concept.…”

“…Additional evidence supporting the view that CPT inhibition is linked to ␤-cell stimulation by glucose can be derived from the fact that, when insulin secretion is suppressed, such as during chronic hyperlipidemia, the CPT-1 gene is upregulated in association with enhanced fat oxidation in the ␤-cell (4). The importance of CPT-1 in ␤-cell glucose signaling is further underscored by the finding that blocking the penultimate step (ATP-citrate lyase) in malonyl-CoA synthesis curtails glucose-sensitive insulin release (8,15). Conversely, CPT-1 overexpression in INS-1 insulinoma cells not only results in exaggerated fatty acid oxidation rates but also impaired glucose-stimulated insulin secretion (37).…”

TNF‐α inhibits glucose‐induced insulin secretion in a pancreatic β‐cell line (INS‐1)

“…ACC is the key enzyme for the production of malonyl-CoA, which is thought to be the coupler for glucose-stimulated insulin secreti ~n [19,20]. Further experimental evidence is required as to the rc echanism of TNF inhibition of glucose-induced insulin secretim.…”

The Mitochondrial Carnitine Palmitoyltransferase System — From Concept to Molecular Analysis

“…l), has all of the enzymes necessary to convert a portion of the glycolytically derived pyruvate into malonyl-CoA which, in turn, suppresses the activity of CPT I and causes elevation of the cytosolic concentration of LCFA-CoA. Current thinking is that LCFA-CoAs act to stimulate exocytosis of insulin granules by a mechanism(s) still to be elucidated and discussed in [31,321. If, as we suspect, this concept has validity, it brings to light a hitherto unrecognized feature of fatty acid metabolism in the workings of the pancreatic p-cell (see also [33]) and confers on the malonyl-CoNCPT I partnership a central role in the regulation of insulin secretion.…”