Translocation-arrested Apolipoprotein B Evades Proteasome Degradation via a Sterol-sensitive Block in Ubiquitin Conjugation

Du, Emma Z.; Fleming, James F.; Wang, Shui-Long; Spitsen, Gary M.; Davis, Roger J.

doi:10.1074/jbc.274.3.1856

Cited by 29 publications

(21 citation statements)

References 57 publications

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“…Our findings are the first to show that in vivo deletion of MTP function (either by Cre -mediated gene disruption or chemical inhibition) blocked hepatic secretion of apoB-100 without causing apoB to accumulate in the ER. These findings are consistent with the notion that while loss of MTP function blocks apoB translocation, apoB does not accumulate in the ER (21,25,(43)(44)(45) because it is cotranslationally degraded (30,37,46,47). Our finding that interruption of MTP function results in the rapid and efficient degradation of secretionincompetent apoB in vivo explains why apoB does not ac- cumulate in hepatic ER.…”

Section: Discussionsupporting

confidence: 91%

Blocking microsomal triglyceride transfer protein interferes with apoB secretion without causing retention or stress in the ER

Liao

Hui

Young

et al. 2003

Journal of Lipid Research

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102

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Microsomal triglyceride transfer protein (MTP)is an intraluminal protein in the endoplasmic reticulum (ER) that is essential for the assembly of apolipoprotein B (apoB)-containing lipoproteins. In this study, we examine how the livers of mice respond to two distinct methods of blocking MTP function: Cre -mediated disruption of the gene for MTP and chemical inhibition of MTP activity. Blocking MTP significantly reduced plasma levels of triglycerides, cholesterol, and apoB-containing lipoproteins in both wild-type C57BL/6 and LDL receptor-deficient mice. While treating LDL receptor-deficient mice with an MTP inhibitor for 7 days lowered plasma lipids to control levels, liver triglyceride levels were increased by only 4-fold. Plasma levels of apoB-100 and apoB-48 fell by Ͼ 90% and 65%, respectively, but neither apoB isoform accumulated in hepatic microsomes. Surprisingly, loss of MTP expression was associated with a nearly complete absence of apoB-100 in hepatic microsomes. Levels of microsomal luminal chaperone proteins [e.g., protein disulfide isomerase, glucoseregulated protein 78 (GRP78), and GRP94] and cytosolic heat shock proteins (HSPs) (e.g., HSP60, HSC, HSP70, and HSP90) were unaffected by MTP inhibition. These findings show that the liver responds rapidly to inhibition of MTP by degrading apoB and preventing its accumulation in the ER.The rapid degradation of secretion-incompetent apoB in the ER may block the induction of proteins associated with unfolded protein and heat shock responses. VLDLs produced by the liver are the major source of LDLs in the plasma, which are causally related to the development of atherosclerotic cardiovascular disease (1). The importance of the hepatic secretion of apolipoprotein B (apoB) in cardiovascular disease was recognized in early studies of abetalipoproteinemic patients, who lack the ability to secrete apoB-containing lipoproteins (2) and are markedly resistant to cardiovascular disease (3). Subsequent studies showed that specific mutations in the microsomal triglyceride transfer protein (MTP) gene are responsible for abetalipoproteinemia (4,5). MTP exists in a functional complex with protein disulfide isomerase (PDI) (6, 7). The loss of MTP function blocks the secretion of apoB-containing lipoproteins from both the liver and the intestine (5). Apart from neuropathy, which can be prevented by vitamin E supplements (8) and moderate steatosis in enterocytes and hepatocytes, abetalipoproteinemia is not usually associated with liver failure or cirrhosis (3). The absence of severe symptoms has suggested that inactivation of MTP might be a useful strategy for combating hyperlipidemia and cardiovascular disease.Several chemical inhibitors of the lipid transfer activity of MTP have been developed (9-12). Many of these inhibitors lower plasma lipid levels in animal models (11-13). Especially encouraging results were obtained in Watanabe-heritable hyperlipidemic rabbits, a model of homozygous familial hypercholesterolemia (13). Administration of an MTP inhibitor to Watan...

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Section: Discussionsupporting

confidence: 91%

Blocking microsomal triglyceride transfer protein interferes with apoB secretion without causing retention or stress in the ER

Liao

Hui

Young

et al. 2003

Journal of Lipid Research

Self Cite

102

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“…Moreover, two other agents, ␤ CD and apoA-I, were also used to remove rather than deliver cholesterol to the HepG2 cells, and these produced the same effect on bile acid synthesis as HDL3. With regard to apoB-100 metabolism, in CHO cells expressing apoB53, but not MTP, cholesterol 7 ␣ -hydroxylase protected against conjugation of the translocation arrested apoB53 with ubiquitin, and therefore reduced proteosome mediated degradation (22). On this basis, Davis has suggested that there is a direct relation between cholesterol 7 ␣ -hydroxylase activity and apoB-100 secretion and that this explains the increased hepatic triglyceride secretion in familial hypertriglyceridemia (23).…”

Section: Discussionmentioning

confidence: 99%

Effects on apoB-100 secretion and bile acid synthesis by redirecting cholesterol efflux from HepG2 cells

Sniderman

Zu-jun

Genest

et al. 2003

Journal of Lipid Research

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This study determined the effects of apoA-I, HDL3, or hydroxy-␤ -cyclodextrin on apoB-100 secretion and bile acid synthesis by HepG2 cells. The principal observations were that: 1 ) ApoB-100 secretion into the medium was significantly less after the addition of any of the three agents. 2 ) Triglyceride mass was not significantly changed from control in the medium but was significantly, although modestly, reduced in the cells. 3 ) Neither free cholesterol (FC) nor cholesteryl ester (CE) mass in the medium was changed; by contrast, CE mass was reduced within the cells although FC was not. 4 ) Although the total mass of cholesterol in the medium was unaffected, the proportion associated with apoB-100 was reduced, whereas the proportion associated with the non-apoB-100 fraction was increased. 5 ) There was also an unanticipated, but substantial, increase in bile acid synthesis induced by apoA-I, HDL3, or hydroxy-␤ -cyclodextrin, which was time and concentration dependent, and which was associated with marked increases in cholesterol 7 ␣ -hydroxylase activity. There were no significant changes in ACAT activity and only modest increases in HMG-CoA reductase activity. These findings support previous clinical observations that an elevated apoB-100 can accompany a low HDL cholesterol in normotriglyceridemic subjects. They also point to physiologically important, although still only partially understood, metabolic relationships amongst hepatic apoB-100 secretion, cholesterol efflux, and bile acid synthesis. -Sniderman, A. D., Z. Zhang, J. Genest, and K. Cianflone. Effects on apoB-100 secretion and bile acid synthesis by redirecting cholesterol efflux from HepG2 cells. J. Lipid Res. 2003. 44: 527-532.

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“…Properties of the ER membrane subject to possible alteration by oxysterols may include the width, fluidity, packing density, or protein density of the ER membrane. The observation that oxysterols, under certain genetic conditions, affect the stability and cellular localization of several membrane proteins not related to HMGR provides modest evidence for such a possibility (52).…”

Section: Discussionmentioning

confidence: 99%

An Oxysterol-derived Positive Signal for 3-Hydroxy- 3-methylglutaryl-CoA Reductase Degradation in Yeast

Gardner

Shan²,

Matsuda

et al. 2001

Journal of Biological Chemistry

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Sterol synthesis by the mevalonate pathway is modulated, in part, through feedback-regulated degradation of 3-hydroxy-3-methylglutaryl-CoA reductase (HMGR). In mammals, both a non-sterol isoprenoid signal derived from farnesyl diphosphate (FPP) and a sterol-derived signal appear to act together to positively regulate the rate of HMGR degradation. Although the nature and number of sterol-derived signals are not clear, there is growing evidence that oxysterols can serve in this capacity. In yeast, a similar non-sterol isoprenoid signal generated from FPP acts to positively regulate HMGR degradation, but the existence of any sterol-derived signal has thus far not been revealed. We now demonstrate, through the use of genetic and pharmacological manipulation of oxidosqualene-lanosterol cyclase, that an oxysterol-derived signal positively regulated HMGR degradation in yeast. The oxysterol-derived signal acted by specifically modulating HMGR stability, not endoplasmic reticulum-associated degradation in general. Direct biochemical labeling of mevalonate pathway products confirmed that oxysterols were produced endogenously in yeast and that their levels varied appropriately in response to genetic or pharmacological manipulations that altered HMGR stability. Genetic manipulation of oxidosqualene-lanosterol cyclase did result in the buildup of detectable levels of 24,25-oxidolanosterol by gas chromatography, gas chromatography-mass spectroscopy, and NMR analyses, whereas no detectable amounts were observed in wild-type cells or cells with squalene epoxidase down-regulated. In contrast to mammalian cells, the yeast oxysterol-derived signal was not required for HMGR degradation in yeast. Rather, the function of this second signal was to enhance the ability of the FPP-derived signal to promote HMGR degradation. Thus, although differences do exist, both yeast and mammalian cells employ a similar strategy of multiinput regulation of HMGR degradation.

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Translocation-arrested Apolipoprotein B Evades Proteasome Degradation via a Sterol-sensitive Block in Ubiquitin Conjugation

Cited by 29 publications

References 57 publications

Blocking microsomal triglyceride transfer protein interferes with apoB secretion without causing retention or stress in the ER

Blocking microsomal triglyceride transfer protein interferes with apoB secretion without causing retention or stress in the ER

Effects on apoB-100 secretion and bile acid synthesis by redirecting cholesterol efflux from HepG2 cells

An Oxysterol-derived Positive Signal for 3-Hydroxy- 3-methylglutaryl-CoA Reductase Degradation in Yeast

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