The roles of different protein kinases and of calmodulin in the effects of Ca2+ mobilization on 3-hydroxy-3-methylglutaryl-CoA reductase activity in isolated rat hepatocytes

Zammit, Victor A.; Caldwell, A M

doi:10.1042/bj2730485

Cited by 11 publications

(13 citation statements)

References 21 publications

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“…This decrease was very similar to the decrease in total HMG-CoA reductase activity observed routinely (44.3 + 3.2%; n = 12; see [1,2]).…”

Section: Quantification Of Immunoreactive Hmg-coa Reductase In Hepatosupporting

confidence: 88%

“…Consequently, it is the depletion of Ca2+ from the ER, which in the hepatocyte is extensive, that could affect the rate of protein synthesis. This theory [2,3] emerged from experiments in which hepatocytes were first treated with EGTA to deplete them of Ca2+ and then had Ca2' added back to them in excess of the amount of EGTA present. We have sought to explore the mechanism further through the use of more gentle conditions, which did not alter the basal rate of protein synthesis and which did not result in Ca2+ depletion of the hepatocytes.…”

Section: Discussionmentioning

confidence: 99%

“…Although some progress has been made in identifying the role of individual protein kinases and phosphatases in the first of these responses [1,2], the mechanism through which a rapid loss of enzyme protein could be achieved remains to be investigated. Previous studies on the possible connection between increased phosphorylation of the enzyme and loss of its activity have concentrated on the role of increaed protein degradation [3][4][5][6].…”

Section: Introductionmentioning

confidence: 99%

“…However, it is equally possible that Ca2+ mobilization acts via a decrease in the rate of synthesis of HMG-CoA reductase. Indeed, preliminary observations indicated that incubations of hepatocytes with inhibitors either of Ca2l-dependent cytosolic proteinases or of lysosomal proteolysis were both ineffective in preventing the action of Ca2+ mobilization on the loss of HMG-CoA reductase in isolated hepatocytes [2]. A third possibility exists, namely that the decrease in total HMG-CoA reductase activity is unrelated to a decrease in the amount of protein, but results from masking of the activity.…”

Section: Introductionmentioning

confidence: 99%

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Rapid decrease in the expression of 3-hydroxy-3-methylglutaryl-CoA reductase protein owing to inhibition of its rate of synthesis after Ca2+ mobilization in rat hepatocytes. Inability of taurolithocholate to mimic the effect

Zammit

Caldwell

Kolodziej

1991

Biochemical Journal

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The mechanisms through which Ca2+ mobilization in rat hepatocytes results in the loss of total activity of 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase [Zammit & Caldwell (1990) Biochem. J. 269, 373-379] were investigated. The loss of total activity was shown to be paralleled by an equal loss of immunoreactive HMG-CoA reductase protein after exposure of hepatocytes to optimal concentrations of vasopressin plus glucagon for 40 min. This loss of enzyme protein was due to an inhibition of enzyme synthesis; the rate of degradation was unaffected. Other Ca(2+)-mobilizing conditions (phenylephrine, glucagon, vasopressin added singly and A23187) also resulted in graded inhibition of synthesis of HMG-CoA reductase. These effects were accentuated by omission of Ca2+ from the cell incubation medium, suggesting that it is the depletion of an intracellular InsP3-sensitive pool of Ca2+ to which synthesis of HMG-CoA reductase is sensitive. In agreement with this we found that t-butylhydroxybenzoquinone, which inhibits the activity of the Ca(2+)-ATPase of the endoplasmic-reticular membrane, mimicked the action of Ca(2+)-mobilizing hormones. However, taurolithocholate, which transiently mobilizes Ca2+ from the same pool, was ineffective. All these effects on HMG-CoA reductase were accompanied by parallel inhibition of 35S incorporation from [35S]methionine into total protein, suggesting that inhibition of reductase synthesis formed part of a generalized response of the hepatocyte to Ca2+ mobilization. Inhibition of the rate of synthesis of HMG-CoA reductase was, however, more responsive to Ca2+ mobilization in the absence of added Ca2+ from the extracellular medium. The concentrations of vasopressin required to elicit the inhibition of synthesis of HMG-CoA reductase were of the same order as those that elicited activation of glycogen phosphorylase in hepatocytes.

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“…This decrease was very similar to the decrease in total HMG-CoA reductase activity observed routinely (44.3 + 3.2%; n = 12; see [1,2]).…”

Section: Quantification Of Immunoreactive Hmg-coa Reductase In Hepatosupporting

confidence: 88%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Rapid decrease in the expression of 3-hydroxy-3-methylglutaryl-CoA reductase protein owing to inhibition of its rate of synthesis after Ca2+ mobilization in rat hepatocytes. Inability of taurolithocholate to mimic the effect

Zammit

Caldwell

Kolodziej

1991

Biochemical Journal

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“…In agreement with the findings of others, the addition of HDL to cultured cells promoted an increase in cholesterol synthesis (53,54); however, this stimulatory effect of HDL was fully inhibited by the enrichment of HDL with PI. Calcium mobilization from the ER has been reported to promote the catabolism of HMG-CoA reductase (55)(56)(57)(58), and therefore PI may decrease cholesterol synthesis in hepatocytes by modulating intracellular calcium levels. Alternatively, increased cholesterol influx into the cells could directly decrease the activity of HMG-CoA reductase at a gene-regulatory level (59)(60)(61).…”

Section: Discussionmentioning

confidence: 99%

Phosphatidylinositol promotes cholesterol transport and excretion

Burgess¹,

Boucher

Neville³

et al. 2003

Journal of Lipid Research

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Administration of phosphatidylinositol (PI) toNew Zealand white rabbits increases HDL negative charge and stimulates reverse cholesterol transport. Intravenously administered PI (10 mg/kg) associated almost exclusively with the HDL fraction in rabbits. PI promoted an increase in the hepatic uptake of plasma free cholesterol (FC) and a 21-fold increase in the biliary secretion of plasma-derived cholesterol. PI also increased cholesterol excretion into the feces by 2.5-fold. PI directly affects cellular cholesterol metabolism. In cholesterol-loaded macrophages, PI stimulated cholesterol mass efflux to lipid-poor reconstituted HDL. PI was about half as effective as cAMP at stimulating efflux, and the effects of cAMP and PI were additive. In cultured HepG2 cells, PI-enriched HDL also enhanced FC uptake from HDL by 3-fold and decreased cellular cholesterol synthesis and esterification. PI enrichment had no effect on the selective uptake of cholesterol esters or on the internalization of HDL particles. PI-dependent metabolic events were efficiently blocked by inhibitors of protein kinase C and the inositol signaling cascade. The data suggest that HDL-PI acts via cell surface ATP binding cassette transporters and signaling pathways to regulate both cellular and intravascular cholesterol homeostasis. It has been known for over 30 years that the altered lipoprotein metabolism in many dyslipidemic states is associated with abnormally charged lipoprotein particles (1). There is now accumulating evidence that this abnormal charge may directly contribute to aberrant lipoprotein metabolism (2-5). Lipoproteins all exhibit a net negative charge, and this charge is determined by both the apolipoprotein and lipid constituents of the lipoprotein particle (6-8). The primary anionic lipid in lipoprotein particles is phosphatidylinositol (PI). While PI is a minor constituent (3-7%) of lipoprotein phospholipids (7, 9), studies suggest that it may be a critical component of chyle and an important regulator of lipoprotein secretion (10, 11). Our work has shown that HDL charge directly affects lipid metabolism by controlling interactions with interfacial enzymes (12-15) and cell surface molecules (16,17). It is now clear that PI affects lipoprotein metabolism both by controlling interfacial interactions and uniquely regulating intracellular signaling pathways.We have previously reported that a single intravenous injection of PI liposomes into fasted rabbits increases the net negative surface charge of HDL and almost completely inhibits lecithin:cholesterol acyltransferase (LCAT) (18). PI therefore directly acts to block the synthesis and storage of cholesteryl ester in the blood stream. In addition, PI appeared to stimulate reverse cholesterol transport (RCT) by promoting a 30-fold increase in the rate of clearance of free cholesterol (FC) from the circulation (18). Previous work has shown that infusion of lecithin liposomes can also promote cholesterol transport; however, the doses utilized to obtain the effect were about 30-fo...

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Harlequin Ichthyosis

Dale

Kam²

1993

Arch Dermatol

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The roles of different protein kinases and of calmodulin in the effects of Ca2+ mobilization on 3-hydroxy-3-methylglutaryl-CoA reductase activity in isolated rat hepatocytes

Cited by 11 publications

References 21 publications

Rapid decrease in the expression of 3-hydroxy-3-methylglutaryl-CoA reductase protein owing to inhibition of its rate of synthesis after Ca2+ mobilization in rat hepatocytes. Inability of taurolithocholate to mimic the effect

Rapid decrease in the expression of 3-hydroxy-3-methylglutaryl-CoA reductase protein owing to inhibition of its rate of synthesis after Ca2+ mobilization in rat hepatocytes. Inability of taurolithocholate to mimic the effect

Phosphatidylinositol promotes cholesterol transport and excretion

Harlequin Ichthyosis

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