The physiological and molecular regulation of lipoprotein assembly and secretion

Blasiole, Daniel A.; Davis, Roger J.; Attie, Alan D.

doi:10.1039/b700706j

Cited by 103 publications

(73 citation statements)

References 183 publications

(218 reference statements)

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“…4d). Consistent with these data, the content of apolipoprotein (apo) B, the key structural protein in the formation of VLDL 40 , in the VLDL fractions was markedly decreased in Ldlr À / À /Retnla-Tg mice compared with Ldlr À / À mice (Fig. 4d, see inset).…”

Section: Resultssupporting

confidence: 74%

The adipokine Retnla modulates cholesterol homeostasis in hyperlipidemic mice

et al. 2014

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Hyperlipidemia is a well-recognized risk factor for atherosclerosis and can be regulated by adipokines. Expression of the adipokine resistin-like molecule alpha (Retnla) is regulated by food intake; whether Retnla has a role in the pathogenesis of hyperlipidemia and atherosclerosis is unknown. Here we report that Retnla has a cholesterol-lowering effect and protects against atherosclerosis in low-density lipoprotein receptor-deficient mice. On a high-fat diet, Retnla deficiency promotes hypercholesterolaemia and atherosclerosis, whereas Retnla overexpression reverses these effects and improves the serum lipoprotein profile, with decreased cholesterol in the very low-density lipoprotein fraction concomitant with reduced serum apolipoprotein B levels. We show that Retnla upregulates cholesterol-7-a-hydroxylase, a key hepatic enzyme in the cholesterol catabolic pathway, through induction of its transcriptional activator liver receptor homologue-1, leading to increased excretion of cholesterol in the form of bile acids. These findings define Retnla as a novel therapeutic target for treating hypercholesterolaemia and atherosclerosis.

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Section: Resultssupporting

confidence: 74%

The adipokine Retnla modulates cholesterol homeostasis in hyperlipidemic mice

et al. 2014

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“…Mutation or knockout of these factors results in embryonic lethality or osteogenesis imperfecta, which clearly shows their importance for productive procollagen folding and maturation (Nagai et al 2000;Morello et al 2006;Cabral et al 2007;Choi et al 2009). Microsomal triglyceride transfer protein (MTP) plays a pivotal role in lipoprotein assembly, and receptorassociated protein (RAP) participates in the maturation of several membrane receptor proteins, such as low-density lipoprotein receptor-related protein (LRP) and lipoprotein receptor 11 (SorLA/LR11) (Orlando 2004;Blasiole et al 2007). …”

Section: Other Specific Chaperonesmentioning

confidence: 99%

Protein Folding and Quality Control in the ER

Araki

Nagata

2011

Cold Spring Harbor Perspectives in Biology

327

285

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The endoplasmic reticulum (ER) uses an elaborate surveillance system called the ER quality control (ERQC) system. The ERQC facilitates folding and modification of secretory and membrane proteins and eliminates terminally misfolded polypeptides through ER-associated degradation (ERAD) or autophagic degradation. This mechanism of ER protein surveillance is closely linked to redox and calcium homeostasis in the ER, whose balance is presumed to be regulated by a specific cellular compartment. The potential to modulate proteostasis and metabolism with chemical compounds or targeted siRNAs may offer an ideal option for the treatment of disease.

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“…Apolipoprotein B (apoB) 3 is the major protein component of very low density lipoprotein (VLDL), the triglyceride-enriched lipoprotein particle produced by the liver. apoB is essential for the assembly and secretion of nascent VLDL particles (1)(2)(3).…”

mentioning

confidence: 99%

“…apoB is essential for the assembly and secretion of nascent VLDL particles (1)(2)(3). apoB is constitutively expressed, and its stability is regulated through co-and post-translational degradation (4).…”

mentioning

confidence: 99%

Regulation of ApoB Secretion by the Low Density Lipoprotein Receptor Requires Exit from the Endoplasmic Reticulum and Interaction with ApoE or ApoB

Blasiole¹,

Oler

Attie

2008

Journal of Biological Chemistry

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Apolipoprotein B (apoB) is required for the hepatic assembly and secretion of very low density lipoprotein (VLDL). The LDL receptor (LDLR) promotes post-translational degradation of apoB and thereby reduces VLDL particle secretion. We investigated the trafficking pathways and ligand requirements for the LDLR to promote degradation of apoB. We first tested whether the LDLR drives apoB degradation in an endoplasmic reticulum (ER)-associated pathway. Primary mouse hepatocytes harboring an ethyl-nitrosourea-induced, ER-retained mutant LDLR secreted comparable levels of apoB with LDLR-null hepatocytes, despite reduced secretion from cells expressing the wild-type LDLR. Additionally, treatment of cells with brefeldin A inhibited LDLR-dependent degradation. However, this rescue was reversible, and degradation of apoB occurred upon removal of brefeldin A. To characterize the lipoprotein reuptake pathway of degradation, we employed an LDLR mutant defective in constitutive endocytosis and internalization of apoB. This mutant was as effective in reducing apoB secretion as the wild-type LDLR. However, the effect was dependent on apolipoprotein E (apoE) as only the wild-type LDLR, and not the endocytic mutant, reduced apoB secretion in apoE-null cells. Treatment with heparin rescued a pool of apoB in cells expressing the endocytic mutant, indicating that reuptake of VLDL via apoE still occurs with this mutant. Finally, an LDLR mutant defective in binding apoB but not apoE reduced apoB secretion in an apoE-dependent manner. Together, these data suggest that the LDLR directs apoB to degradation in a post-ER compartment. Furthermore, the reuptake mechanism of degradation occurs via internalization of apoB through a constitutive endocytic pathway and apoE through a ligand-dependent pathway. Apolipoprotein B (apoB)3 is the major protein component of very low density lipoprotein (VLDL), the triglyceride-enriched lipoprotein particle produced by the liver. apoB is essential for the assembly and secretion of nascent VLDL particles (1-3). apoB is constitutively expressed, and its stability is regulated through co-and post-translational degradation (4). Therefore, the number of VLDL particles secreted is a function of the proportion of apoB that escapes degradation.The LDL receptor (LDLR) is a ubiquitously expressed protein responsible for the clearance of cholesterol-rich lipoproteins from the bloodstream through its ligands, apoB and apolipoprotein E (apoE). A loss in LDLR activity, as occurs in humans with familial hypercholesterolemia (FH), results in a defect in LDL clearance (5). In addition to its role in mediating lipoprotein clearance, the LDLR also regulates VLDL secretion. Studies in humans (6 -8), mice (9 -11), primary hepatocytes (12-15), and human hepatoma cells (16) have revealed that the loss of LDLR activity leads to increased secretion of VLDL particles, due to a decrease in the degradation of apoB. The particles secreted from livers lacking LDLR activity are small (6, 10, 14) and have decreased triglyceride content ...

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The physiological and molecular regulation of lipoprotein assembly and secretion

Cited by 103 publications

References 183 publications

The adipokine Retnla modulates cholesterol homeostasis in hyperlipidemic mice

The adipokine Retnla modulates cholesterol homeostasis in hyperlipidemic mice

Protein Folding and Quality Control in the ER

Regulation of ApoB Secretion by the Low Density Lipoprotein Receptor Requires Exit from the Endoplasmic Reticulum and Interaction with ApoE or ApoB

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