Augmentation of Ca2+-Induced Microsomal Triglyceride Transfer Protein Activity by Glucose Supply Enhances Hypertriglyceridemia in Vivo

Abstract

We have investigated possible roles of intra-glucose supply on microsomal triglyceride (TG) transfer protein (MTP) in the secretion of TG-rich very low-density lipoprotein (VLDL) from the liver. Due to the activation of MTP, TG and apolipoprotein B (apoB) in the liver are assembled into VLDL and then the VLDL is transferred into the blood stream. High MTP activity can increase the release of VLDL into the blood stream, and this would lead high levels of TG and apoB in the blood. High MTP activity was found when the liver (or hepatocytes) contained a high level of total Ca 2؉ as a response of glucose administration. However, the MTP activity was reduced in response to the calmodulin antagonist N-(6-aminohexyl)-5-chloro-1-naphthalene sulfonamide (W-7, K i ‫52؍‬ m mM), the intracellular Ca 2؉ chelator BAPTA-AM, and the extracellular Ca 2؉ chelator EDTA. These suggested that there might be a very close relationship between high MTP activity and high Ca 2؉ level in the liver by glucose administration. Glucose-derived hyperglycemic condition resulted from those elevations of TG and total cholesterol in the liver. This hyperglycemic phenomenon may be associated with the increase of TG and apoB levels in blood. The possibility for the regulation of VLDL formation in the liver and, further, those related circulatory diseases due to the excess of VLDL in the blood stream by controlling MTP activity in association with Ca 2؉ was investigated.

The opposite correlation between calcium ion and cyclic-AMP regarding the activation of microsomal triglyceride transfer protein in rat liver

“…This means that MTP mRNA is not related with MTP activity, but other factors like glucose-mediated metabolites regulation may be involved in MTP activation. As described in our previous reports, hepatocellular Ca 2+ acts as a stimulatory factor of MTP activity (7,8). This study found that MTP activity was increased in the livers of GR containing high levels of Ca 2+ ( Fig.…”

“…2A) When a 10% glucose solution was administered, insulin increased in GR serum (7). Furthermore, insulin increases the level of liver Ca 2+ (13,14).…”

“…It is known that fructose or glucose treatment increases the level of TG in rat liver (5,6). Glucose treatment also increased the level of insulin in serum, an event directly involved in the occurrence of hypertriglyceridemia (7). Recently, we have reported that MTP activity, which promotes hypertriglyceridemia, is stimulated by increased Ca 2+ levels (7) in the liver as well as increased hepatocytes in rats under insulin resistance.…”

“…Glucose treatment also increased the level of insulin in serum, an event directly involved in the occurrence of hypertriglyceridemia (7). Recently, we have reported that MTP activity, which promotes hypertriglyceridemia, is stimulated by increased Ca 2+ levels (7) in the liver as well as increased hepatocytes in rats under insulin resistance. On the contrary, Ca 2+ -induced MTP activity was inhibited in response to the intracellular Ca 2+ chelator BAPTA-AM, the extracellular Ca 2+ chelator EDTA, as well as the calmodulin antagonist W-7 (7,8), all of which suggest Ca 2+ directly increases MTP activity.…”

“…Recently, we have reported that MTP activity, which promotes hypertriglyceridemia, is stimulated by increased Ca 2+ levels (7) in the liver as well as increased hepatocytes in rats under insulin resistance. On the contrary, Ca 2+ -induced MTP activity was inhibited in response to the intracellular Ca 2+ chelator BAPTA-AM, the extracellular Ca 2+ chelator EDTA, as well as the calmodulin antagonist W-7 (7,8), all of which suggest Ca 2+ directly increases MTP activity. On the other hand, the activation of hepatocellular adenylate cyclase, which produces cAMP from ATP, has been reported to suppress the secretion of TG-rich VLDL (9).…”