Effects of nonketotic streptozotocin diabetes on apolipoprotein B synthesis and secretion by primary cultures of rat hepatocytes.

Sparks, Janet D.; Sparks, Charles E.; Bolognino, Mary; Roncone, A.; Jackson, Timothy; Amatruda, John M.

doi:10.1172/jci113597

Cited by 38 publications

(42 citation statements)

References 37 publications

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“…However, apoB secretion is regulated by post-translational mechanisms without the protein being stored in secretory vesicles. In addition to lipids and MTP activity, several stimuli including insulin, apolipoproteins, chaperone proteins, and cytokines such as tumor necrosis factor and interleukin-1␤ can alter the secretion of apoB (27,28). Tumor necrosis factor and interleukin-1␤ decrease apoB secretion via epidermal growth factor receptor signaling (28), and these two cytokines also increase levels of ferritins (20).…”

Section: The Block In Apob Secretion Induced By Ferritin H or L Is Nomentioning

confidence: 99%

Ferritins Can Regulate the Secretion of Apolipoprotein B

Hevi

Chuck

2003

Journal of Biological Chemistry

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Apolipoprotein B is secreted with atherogenic lipids as lipoprotein particles from hepatocytes. Regulation of the secretion of apolipoprotein B is largely post-translational and reflects the balance between processes that leads to particle assembly or to intracellular degradation. Previously, we conducted a proteomic screen to find proteins that bind apolipoprotein B in rat liver microsomes. We identified ferritin heavy and light chains in this screen among other proteins and showed that the two ferritins bind apolipoprotein B directly in vitro. In hepatocytes and other cells, ferritin heavy and light chains form cytosolic cages that store iron. We now show that ferritin heavy or light chains post-translationally inhibit the secretion of apolipoprotein B without altering the export of other hepatic proteins including albumin, factor XIII, and apolipoprotein A-I. This inhibition of apolipoprotein B secretion is not due to diminished lipid synthesis and can be partially overcome by stimulating triglyceride synthesis. The block in apolipoprotein B secretion by ferritins leads to an increase in endoplasmic reticulum-associated degradation of the apolipoprotein. Thus, despite being cytosolic proteins without known chaperone activity, ferritins can specifically regulate the secretion of apolipoprotein B post-translationally. The metabolic pathways for iron storage and intercellular cholesterol and triglyceride transport could intersect. Apolipoprotein B (apoB)1 is the large (molecular mass greater than 500 kDa), hydrophobic protein that is secreted with cholesterol esters and triglycerides in very low density lipoprotein particles (1). Regulation of the secretion of apoB from hepatocytes occurs largely post-translationally (2). Newly synthesized apoB can be assembled with lipids into lipoprotein particles or degraded intracellularly (3, 4), and it is the balance assembly and degradation that determines secretion. Since cholesterol esters and triglycerides can only be secreted into the bloodstream with apoB, factors that regulate the secretion of this protein likewise impact plasma levels of these atherogenic lipids.In HepG2 cells, unassembled apoB can be targeted for endoplasmic reticulum-associated degradation (ERAD) via the ubiquitin-proteasome pathway (5-8). ApoB is marked with ubiquitin for degradation even before it is finished being translated (7, 9, 10) while the protein is still in the translocation channel (8, 11). Furthermore, factors that slow the translocation of apoB increase the number of ubiquitin-conjugated apoB molecules marked for degradation by proteasomes (8) suggesting that translocation is a point of regulation of secretion. Other factors also regulate secretion since some ubiquitin-conjugated apoB can be deubiquitinylated and secreted (11). In HepG2 cells, other non-ERAD routes for disposal exist but are not sensitive to agents that inhibit proteasomes (12-15).The intertwined processes of lipidation, folding, translocation, intracellular degradation, quality control, and regulation of the secret...

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Section: The Block In Apob Secretion Induced By Ferritin H or L Is Nomentioning

confidence: 99%

Ferritins Can Regulate the Secretion of Apolipoprotein B

Hevi

Chuck

2003

Journal of Biological Chemistry

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“…The increased rates of delivery of fatty acids to the liver makes this possible. (Although it has been found repeatedly that rates of VLDL-TAG secretion by isolated cultured hepatocytes and the perfused livers obtained from starved and diabetic rats have a much lower rate of secretion of TAG [90][91][92], these experiments may have underestimated the rates attainable, due to the inadequacy of the mixture of substrates provided to these preparations in itro, as demonstrated in [93]. )…”

Section: Acute Changes In Glycerolipid Partitioning During the Prandimentioning

confidence: 99%

Role of insulin in hepatic fatty acid partitioning: emerging concepts

Zammit

1996

Biochemical Journal

115

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“…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).…”

Section: Introductionmentioning

confidence: 99%

“…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). The cause of the hyperlipidemia has been attributed to overall increase in lipoprotein formation (31,32) in combination with defective peripheral and hepatic catabolism of triglyceride-rich lipoproteins and LDL (29,(31)(32)(33)(34)(35). 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).…”

Section: Introductionmentioning

confidence: 99%

“…The cause of the hyperlipidemia has been attributed to overall increase in lipoprotein formation (31,32) in combination with defective peripheral and hepatic catabolism of triglyceride-rich lipoproteins and LDL (29,(31)(32)(33)(34)(35). 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).…”

Section: Introductionmentioning

confidence: 99%

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

Sparks¹,

Zolfaghari²,

Sparks³

et al. 1992

J. Clin. Invest.

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Studies of streptozotocin-induced diabetes in rats have demonstrated that hepatic apo B and apo E production are reduced. To determine if reductions are related to decreases in hepatic mRNAs, we performed blotting analysis of total liver RNA with rat apo B, apo E, and albumin cDNA probes. The expected reduction in albumin mRNA levels to 48% of control livers occurred in diabetic rat liver, while apo B and apo E mRNA levels were unchanged. The proportion of translational stop codon (BSTOP) mRNA averaged 43% of total in diabetic rats similar to control levels. Long-term labeling experiments using JISlmethionine in primary cultures of rat hepatocytes and specific immunoprecipitations demonstrated production of apo B and apo E, and albumin by hepatocytes from diabetic rats was reduced to 37%, 53%, and 23% of controls. Pulse-chase studies, together with mRNA analyses, suggest that reduced hepatic secretion of apo B and apo E in diabetics is primarily a result of impaired translation and not intracellular degradation. Ribosome transit studies directly confirmed the prolonged elongation rates for apo B and apo E mRNAs in hepatocytes derived from diabetic rats. This effect was more pronounced on apo BH (higher molecular weight) than on apo BL (lower molecular weight). Treatment of diabetic rats with insulin for 7 d led to normalization of hepatic albumin mRNA levels with no substantial change in apo E mRNA levels. In contrast, insulin treatment resulted in significant increases in hepatic apo B mRNA over control levels. Results suggest hepatic albumin and apo B mRNA levels are responsive to insulin in the diabetic state. (J.

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Effects of nonketotic streptozotocin diabetes on apolipoprotein B synthesis and secretion by primary cultures of rat hepatocytes.

Cited by 38 publications

References 37 publications

Ferritins Can Regulate the Secretion of Apolipoprotein B

Ferritins Can Regulate the Secretion of Apolipoprotein B

Role of insulin in hepatic fatty acid partitioning: emerging concepts

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

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