The lipolysis/esterification cycle of hepatic triacylglycerol. Its role in the secretion of very-low-density lipoprotein and its response to hormones and sulphonylureas

Abstract

In hepatocyte cultures maintained in the absence of extracellular fatty acids, at least 70 % of the secreted very-low-density lipoprotein (VLDL) triacylglycerol was derived via lipolysis of intracellular triacylglycerol. This proportion was unchanged when the cells were exposed for 24 h to insulin or glucagon, hormones which decreased the overall secretion of intracellular triacylglycerol, or to chloroquine or tolbutamide, agents which inhibit lysosomal lipolysis. The rate of intracellular lipolysis was 2-3-fold greater than that required to maintain the observed rate of triacylglycerol secretion. Most of the fatty acids released were returned to the intracellular pool. Neither insulin nor glucagon had any significant effect on the overall lipolysis and re-esterification of intracellular triacylglycerol. In these cases a greater proportion of the released fatty acids re-entered the cellular pool, rather than being recruited for VLDL assembly. Tolbutamide inhibited intracellular lipolysis, but suppressed VLDL secretion to a greater extent. 3,5-Dimethylpyrazole did not affect lipolysis or VLDL secretion. The increased secretion of VLDL triacylglycerol observed after exposure of cells to insulin for 3 days was not accompanied by an increased rate of intracellular lipolysis. However, a larger proportion of the triacylglycerol secreted under these conditions may not have undergone prior lipolysis. INTRODUCTIONTreatment of hepatocytes in culture with insulin for periods less than 24 h results in a decreased net rate of mobilization of cytosolic triacylglycerol [1] and a decrease in the rate of very-lowdensity lipoprotein (VLDL) lipid [1][2][3][4][5] and apoprotein B (apoB) secretion [6][7][8][9][10]. It has previously been suggested that at least some of the VLDL triacylglycerol is derived from the cytosolic storage pool via lipolysis, followed by re-esterification in the endoplasmic reticulum [11][12][13][14]. There has been no attempt to quantify this in mammalian liver. Glucagon and cyclic AMP

Role of insulin in hepatic fatty acid partitioning: emerging concepts

“…isolated hepatocytes [123] and in i o [124] that only a minor proportion of the flux leading from cytosolic TAG to secreted TAG is due to transfer en bloc of intact molecules of TAG. Rather, the cytosolic TAG has to undergo a degree of hydrolysis and re-esterification before being utilized for secretion.…”

“…The scheme is based on proposals by several authors (see [120][121][122][123][124][125]). Further abbreviations : MAG, monoacylglycerol ; PC, phosphatidylcholine ; PE, phosphatidylethanolamine.…”

Inhibition of liver microsomal carnitine acyltransferases by sulphonylurea drugs

“…Since the physiological role of the microsomal CATs is not yet known it is not possible to tell whether any of the various documented extrapancreatic effects of the sulphonylureas could result from interactions with microsomal CATs. We are however struck by the facts that 5 mM tolbutamide inhibited VLDL secretion by rat hepatocytes by 75% [8] and (at physiological carnitine concentrations) also inhibited the liver microsomal malonyl-CoA-sensitive CAT by 75% (Fig. 1).…”

“…The effect of tolbutamide on the malonyl-CoA-inhibitable transferase was influenced by the phospholipid/detergent environment whereas the effect of glibenclamide was not. Key words: Carnitine acyltransferases; Glibenclamide; Liver; Microsome; Sulphonylureas; Tolbutamide Wiggins and Gibbons [8] have shown that the sulphonylurea drug tolbutamide is able to suppress VLDL triacylglycerol secretion by hepatocytes. Tolbutamide appeared to have two actions.…”

“…Wiggins and Gibbons [8] have shown that the sulphonylurea drug tolbutamide is able to suppress VLDL triacylglycerol secretion by hepatocytes. Tolbutamide appeared to have two actions.…”