Insulin regulates apolipoprotein B turnover and phosphorylation in rat hepatocytes.

Abstract

Our laboratory has previously shown that insulin inhibits the secretion of newly-synthesized and immunoreactive apo B from rat hepatocytes. We have also shown that apo B is secreted as a phosphoprotein and that phosphorylation is increased in hypoinsulinemic nonketotic diabetes. The present studies were conducted to determine whether the ability of insulin to inhibit apo B secretion is related to alterations in apo B turnover and whether insulin itself affects apo B phosphorylation. Pulsechase studies with I35Simethionine in primary cultures of hepatocytes from normal rats in the absence and presence of insulin show that the secretion of apo B100 and apo B48 are inhibited by insulin and that this inhibition may be due in part to enhanced intracellular degradation. In addition, there is a second intracellular apo B48 pool which is not insulin regulated or degraded. In experiments in which hepatocytes were incubated with [32Pjorthophosphate, insulin decreased 32P incorporation into apo B100 (42%) with only small effects on apo B48 (11%). The small insulin effect on apo B48 may relate to an insulin-insensitive apo B48 intracellular pool. These studies show that insulin can affect the intracellular turnover, secretion, degradation, and phosphorylation of apo B and emphasize the differential regulation of apo B100 and apo B48 with regard to these parameters in rat liver. (J. Clin. Invest. 1990.

Hepatic secretion of very-low-density lipoprotein apolipoprotein B-100 studied with a stable isotope technique in men with visceral obesity

“…44 In the present study, the regulation of VLDL apoB secretion appeared to be closely linked with hyperinsulinaemia. Recent in vitro 14,15 and in vivo 16,17 studies have demonstrated that acute hyperinsulinaemia decreases the hepatic secretion of VLDL apoB in the nondiabetic state. By contrast, studies using rat livers VLDL apoB secretion in men with visceral obesity FM Riches et al have shown that in the long-term, insulin stimulates VLDL apoB secretion.…”

“…In vitro studies suggest that the hepatic secretion of VLDL apoB is dependent on the availability of free fatty acids that determine the synthetic rates of both cholesterol esters and triglycerides. 11,13 Both in vitro 14,15 and in vivo 16,17 studies have shown that insulin inhibits the hepatic secretion of VLDL apoB. In vivo data have also shown that enhanced cholesterol synthesis is a feature of insulin resistance 18 and that acute hyperinsulinaemia diminishes the rate of cholesterogenesis as measured by the plasma concentration of mevalonic acid.…”

Impaired fatty acid metabolism in familial combined hyperlipidemia. A mechanism associating hepatic apolipoprotein B overproduction and insulin resistance.

“…Apo B gene defects have been ruled out by linkage analysis in FCH kindreds (40). Several studies have demonstrated that insulin decreases apo B secretion in vitro by enhanced intracellular degradation (41)(42)(43)(44). However, the hyperinsulinemia in FCH may be a consequence of the insulin resistance and this may be associated to impaired metabolism of fatty acids by peripheral cells.…”

Role of insulin in hepatic fatty acid partitioning: emerging concepts

“…Thus, whereas experiments conducted with isolated perfused rat liver showed that insulin stimulates both synthesis and secretion of TAG [136,137], many subsequent studies conducted on cultured hepatocytes have found that insulin, although promoting synthesis of TAG, inhibits its secretion [6,8,133,138,139]. The reasons for this discrepancy between the two sets of data may reside in the use of different experimental systems (perfused liver, cultured cells) and in the choice of the precise perfusion or culture conditions, by different laboratories.…”

“…In addition, it is apparent that TAG synthesis and secretion respond to different concentrations of insulin in cell-culture experiments, higher ones being required to inhibit secretion [8]. There also seems to be disagreement as to whether insulin only affects apoB degradation [139], or whether it also affects apoB synthesis [140]. Moreover, prolonged exposure (5 days) of cultured rat hepatocytes to insulin enhanced apoB %) secretion by promoting apoB mRNA editing [141].…”