INSULIN REGULATES ENZYME-ACTIVITY, MALONYL-COA SENSITIVITY AND MESSENGER-RNA ABUNDANCE OF HEPATIC CARNITINE PALMITOYLTRANSFERASE-I

The regulation of hepatic mitochondrial carnitine palmitoyl-transferas e-I (CPT-I) was studied in rats during starvation and insulin-dependen t diabetes and in rat H4IIE cells. The V-max. for CPT-I in hepatic mit ochondrial outer membranes isolated from starved and diabetic rats inc reased 2- and 3-fold respectively over fed control values with no chan ge in K-m values for substrates. Regulation of malonyl-CoA sensitivity of CPT-I in isolated mitochondrial outer membranes was indicated by a n 8-fold increase in K-i during starvation and by a 50-fold increase i n K-i in the diabetic state. Peroxisomal and microsomal CPT also had d ecreased sensitivity to inhibition by malonyl-CoA during starvation. C PT-I mRNA abundance was 7.5 times greater in livers of 48-h-starved ra ts and 14.6 times greater in livers of insulin-dependent diabetic rats compared with livers of fed rats. In H4IIE cells, insulin increased C PT-I sensitivity to inhibition by malonyl-CoA in 4 h, and sensitivity continued to increase up to 24 h after insulin addition. CPT-I mRNA le vels in H4IIE cells were decreased by insulin after 4 h and continued to decrease so that at 24 h there was a 10-fold difference. The half-l ife of CPT-I mRNA was 4 h in the presence of actinomycin D or with act inomycin D plus insulin. These results suggest that insulin regulates CPT-I by inhibiting transcription of the CPT-I gene.