Inhibition by chloroquine of the secretion of very low density lipoproteins by cultured rat hepatocytes

Nossen, J O; Rustan, Arild C.; Barnard, Tudor; Drevon, Christian A.

doi:10.1016/0167-4889(84)90049-1

Cited by 34 publications

(17 citation statements)

References 42 publications

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“…This difference compared with the present study may be related to the differences in patient characteristics, in particular the prednisolone dose and renal function. Several studies have proposed the possible lipid‐lowering mechanisms of HCQ, including selective inhibition of VLDL secretion or synthesis, 26,27,29 increased LDL receptor activity by reducing lysosomal hydrolysis of cholesterol esters, 30 inhibition of cholesterol synthesis through 2,3 oxidosqualene‐lanosterol cyclase inhibition 31 and improving insulin resistance 32 . The exact one involved in lupus patients is yet to be elucidated in future controlled studies.…”

Section: Discussionmentioning

confidence: 99%

Dyslipidaemia in patients with lupus nephritis

et al. 2011

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Section: Discussionmentioning

confidence: 99%

Dyslipidaemia in patients with lupus nephritis

et al. 2011

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“…The means by which insulin uncouples the synthesis and secretion of triacylglycerol is not clear. Fatty acids released by hepatic lysosomal lipolysis of cytosolic triacylglycerol [100] appear to contribute to VLDL triacylglycerol [101,102] and inhibition of this lipase by insulin [100] might therefore be expected to suppress the secretion of triacylglycerol. There is also some evidence for an impairment of apo B association with triacylglycerol [103], but the intracellular site(s) accommodating this defect have not been investigated.…”

Section: Hormonal Effectsmentioning

confidence: 99%

Assembly and secretion of hepatic very-low-density lipoprotein

Gibbons

1990

Biochemical Journal

276

163

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In contrast to water-soluble fuels such as glucose or ketone bodies, the use of lipids as an energy source for tissues has required the development of complex structures for their transport through the aqueous plasma. In the case of endogenously synthesized triacylglycerol this is achieved by the assembly and secretion of hepatic VLDL which provides the necessary stability in an aqueous medium. An essential component of this assembly process is apo B. Dietary changes which require an increase in hepatic VLDL secretion appear to be accompanied by increases in the availability of functional apo B. Interesting questions relate to: (a) the intracellular site(s) of triacylglycerol association with apo B, and (b) the mechanism(s) by which the availability of functional apo B at this site responds to metabolic and hormonal signals which reflect dietary status and, thus, the need to secrete triacylglycerol. As regards the latter, although in some cases changes in apo B synthesis occur in response to VLDL secretion hepatic apo B mRNA levels appear to be quite stable in vitro. Intracellular switching of apo B between the secretory and degradative pathways may be important in controlling VLDL assembly and post-translational modifications of the apoprotein may also play a role by influencing its ability to bind to triacylglycerol. Transport is not the only problem associated with the utilization of a concentrated energy source such as triacylglycerol and the complex problems of waste product disposal and recycling have to be dealt with. In the case of triacylglycerol, potentially toxic waste products include atherogenic remnants and LDL. The overall problem, then, in the long-term, involves the development of a 'safe' means of utilizing triacylglycerol and this requirement accounts for much of the complexity of plasma lipoprotein metabolism. In this area, the rat could teach the human a few tricks. One of these appears to be the utilization of hepatic apo B48 rather than apo B100 for VLDL assembly in response to increases in the extrahepatic utilization of hepatically synthesized triacylglycerol. Under these conditions, the remnants of hepatic triacylglycerol utilization by peripheral tissues are cleared from the plasma much more readily via a process which seems to involve the cycling of more triacylglycerol back to the liver than that which occurs in humans. The means by which this is achieved, though, are obscure and may involve a chylomicron remnant receptor, the nature of which, itself, remains controversial.(ABSTRACT TRUNCATED AT 400 WORDS)

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“…Hepatocytes were prepared from male albino rats (200-300 g) by collagenase perfusion and plated as described elsewhere (Nossen et al, 1984).…”

Section: Preparation Of Cultured Hepatocytesmentioning

confidence: 99%

“…Triacyl[3H]glycerol was determined by extraction, isolation by t.l.c. and liquidscintillation counting (Nossen et al, 1984). The mass of secreted triacylglycerol was determined by an enzymic method for free glycerol (fluorimetry) (Wieland, 1974).…”

Section: Determination Of Vldl-triacylglycerolmentioning

confidence: 99%

“…VLDL-triacylglycerol secretion was determined by incorporation of [3H]glycerol into triacylglycerol recovered in the medium. After preincubation of cells with this label for 30 min, secretion of VLDL-triacylglycerol was linear with time for at least 2 h and more than 95 % of triacyl[3H]glycerol in the medium appeared in the VLDL fraction (d < 1.006) (Nossen et al, 1984). The rate of appearance of triacyl[3H]glycerol in the medium was therefore taken as a satisfactory estimate for secretion of newly synthesized VLDL-triacylglycerol. Protein content of the dishes was determined with BSA as standard (Lowry et al, 1951).…”

Section: Determination Of Vldl-triacylglycerolmentioning

confidence: 99%

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Calcium-antagonists inhibit secretion of very-low-density lipoprotein from cultured rat hepatocytes

Nossen

Rustan

Drevon³

1987

Biochemical Journal

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The effects of different calcium-antagonists on secretion of very-low-density lipoprotein (VLDL) from cultured rat hepatocytes were examined. Verapamil (an inhibitor of voltage-dependent calcium channels) and EGTA (a calcium chelator) decreased VLDL-triacylglycerol secretion in a concentration-dependent manner, with maximum inhibition (about 90%) at 0.2 mM-verapamil and 5 mM-EGTA. Inorganic calcium-antagonists such as lanthanum, nickel, cobalt and manganese decreased secretion of VLDL-triacylglycerol by 55-95%, whereas the calcium-agonist barium did not affect secretion. Inhibition of VLDL-triacylglycerol secretion appeared within 30 min, without inhibition of triacylglycerol synthesis. Pulse-chase experiments revealed that verapamil and cobalt inhibited the secretory pathway itself. Cobalt showed a concentration-dependent inhibition of VLDL-triacylglycerol secretion, with maximal effect at 8 mM. Although inhibition by cobalt was not completely reversible, Trypan Blue exclusion and lactate dehydrogenase leakage indicated that the hepatocytes were not injured by cobalt or any of the other calcium-antagonists tested. Inhibition of protein synthesis by cycloheximide did not affect triacylglycerol secretion (up to 2 h), and the observed effects were therefore probably not due to impaired production of apolipoproteins. Taken together, these results suggest that calcium is important for secretion of VLDL particles.

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Inhibition by chloroquine of the secretion of very low density lipoproteins by cultured rat hepatocytes

Cited by 34 publications

References 42 publications

Dyslipidaemia in patients with lupus nephritis

Dyslipidaemia in patients with lupus nephritis

Assembly and secretion of hepatic very-low-density lipoprotein

Calcium-antagonists inhibit secretion of very-low-density lipoprotein from cultured rat hepatocytes

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