Insulin effects on apolipoprotein B production by normal, diabetic and treated-diabetic rat liver and cultured rat hepatocytes

Abstract

1. The effect of insulin on apolipoprotein (apo B) secretion was studied in 24 h recirculating liver perfusions of isolated normal, diabetic and insulin-treated diabetic rats. In single perfusions from each group apo B accumulated in the media in a linear fashion. 2 In perfusions of normal rat livers, when the medium contained insulin plus cortisol, apo B production was significantly inhibited (by 35.8%), demonstrating a hormone effect on apo B secretion. 3. In perfusions of diabetic-rat livers, apo B production was decreased to 11.8% of normal when the medium contained no hormones, and was not significantly changed by the addition of insulin plus cortisol to the medium, suggesting that the hormone effect on apo B secretion is missing in long-term hypoinsulinaemic states. 4. Treatment of diabetic rats with daily insulin injection restored apo B production and restored the effect of insulin plus cortisol in the medium to inhibit apo B secretion during perfusion. 5. Parallel studies of apo B secretion with insulin alone, cortisol alone and insulin plus cortisol in the medium were performed in primary cultures of hepatocytes to compare results from liver perfusions. 6. Apo B secretion by hepatocytes from normal, diabetic and treated-diabetic rats was inhibited (by 36.8%, 57.1% and 57.9% respectively) when insulin alone was added to the medium. 7. Insulin plus cortisol inhibited apo B secretion by hepatocytes from normal and treated diabetic rats (by 30.2% and 47.2% respectively), but failed to inhibit apo B secretion by hepatocytes from diabetic rats.

Impaired hepatic apolipoprotein B and E translation in streptozotocin diabetic rats.

“…In order to determine ifthe previously observed reduction in apo B secretion by livers derived from diabetic rats was due to an effect on apo B translation, we examined apo B synthesis in corresponding cultures ofprimary rat hepatocytes. We have previously demonstrated that the reduced hepatic secretion of apo B by liver of diabetic rats is retained by corresponding primary hepatocytes (28,29). Liver perfusions to prepare hepatocytes were carried out 1 h apart so that hepatocytes derived from control and diabetic livers could be cultured under identical experimental conditions.…”

“…VLDL composition is altered in streptozotocin-induced diabetes with a marked reduction in apo E content (29,31,36) which may be a contributory factor to the catabolic defect, as apo E is an important ligand for hepatic lipoprotein receptors (37). Hepatic secretion of VLDL lipid (36,(38)(39)(40)(41) and apo B and E is substantially reduced in both primary cultures of hepatocytes (28,29) and perfused livers derived from diabetic rats (28,36). These findings suggest that the hyperlipidemia of experimental diabetes is primarily a result of the accumulation of intestinally derived chylomicrons and VLDL, and suggest further that the contribution of apo B-containing lipoproteins to the plasma by the liver in the hypoinsulinemic diabetic state is relatively small.…”

“…Existing evidence suggests that hepatic apo B secretion can also be affected posttranslationally through degradation of freshly synthesized apo B (21)(22)(23)(24). Insulin has been shown to reduce hepatic secretion of apo B (22,(25)(26)(27)(28) by stimulation of intracellular degradation (22).…”

“…In order to understand the complex role ofinsulin in regulation of hepatic apo B production we have examined the effects ofhypoinsulinemic diabetes (28,29). This experimental model is of interest because diabetic rats develop significant hyperlipidemia (30)(31)(32) along with increased levels of plasma apo Bcontaining lipoproteins (29,31).…”

Effect of meal sequence on postprandial lipid, glucose and insulin responses in young men

“…One possible mechanism to account for the lower postprandial change in overall total TAG concentration following lunch compared to breakfast is suppression of VLDL-TAG secretion by the liver. This is supported by the observation that addition of insulin to cultured cells (Durrington et al, 1982;Dashti & Wolfbauer, 1987;Sparks et al, 1989;Byrne et al, 1991;Salhanick et al, 1991) and acute hyperinsulinaemia in human subjects (Vogelberg et al, 1978;Lewis et al, 1993Lewis et al, , 1994Shumak et al, 1988;Malmstrom et al, 1997a) suppressed VLDL secretion. Furthermore, Malmstrom et al (1998) showed that hyperinsulinaemia suppressed secretion of VLDL 1 leading to a differential increase in VLDL 2 secretion.…”