Subcellular Localization of “B” Apoprotein of Plasma Lipoproteins in Rat Liver

Alexander, Cheryl Ann; Hamilton, Robert L.; Havel, Richard J.

doi:10.1017/s0424820100051207

Cited by 19 publications

(33 citation statements)

References 22 publications

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“…The assembly of VLDL starts in the ER, and a two-step model for VLDL formation has been widely accepted [1,2]. VLDL assembly begins with the translation and translocation of apoB100 across the rough ER membrane [3].…”

Section: Discussionmentioning

confidence: 99%

“…Of several apolipoproteins, apoB100 (apolipoprotein B 100) is the essential component of VLDL and its metabolites IDL (intermediate-density lipoprotein) and LDL. The assembly of VLDL starts in the ER (endoplasmic reticulum) with MTP (microsomal TAG transfer protein)-mediated partial lipidation of apoB100 and then the bulk of the neutral TAG is added to the poorly lipidated apoB100-containing particle [1][2][3][4][5]. The intracellular site of VLDL maturation remains unclear despite many efforts to identify it.…”

Section: Introductionmentioning

confidence: 99%

“…The intracellular site of VLDL maturation remains unclear despite many efforts to identify it. A number of studies report that VLDL maturation occurs in the ER [2,[6][7][8][9][10][11], whereas other studies suggest that the Golgi is the site where the formation of mature VLDL takes place [12-14a].…”

Section: Introductionmentioning

confidence: 99%

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VLDL exits from the endoplasmic reticulum in a specialized vesicle, the VLDL transport vesicle, in rat primary hepatocytes

Siddiqi

2008

Biochemical Journal

163

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The movement of VLDL [very-LDL (low-density lipoprotein)] from the ER (endoplasmic reticulum) to the Golgi is required for its eventual secretion from hepatocytes and represents a potential target in controlling elevated concentrations of its metabolite LDL, the major determinant of atherosclerosis. To study this process, an in vitro ER-budding assay was developed to examine the generation of the VTV (VLDL transport vesicle) and PTV (protein transport vesicles) using ER isolated from [(14)C]TAG (triacylglycerol) and [(3)H]protein-labelled primary rat hepatocytes. VTVs do not contain albumin, as determined by immunoblots. VTVs were distributed in light-density fractions, whereas PTVs were mainly in the mid-portion of the sucrose gradient. Electron microscopy revealed that VTVs were larger ( approximately 100-120 nm) in size than PTVs ( approximately 55-70 nm). ER from 0.4 mM OA (oleic acid)-treated hepatocytes budded VTVs of a lighter density as compared with VTVs budded from ER of 0.1 mM or 0.004 mM OA-treated hepatocytes. The generation of VTVs from rat hepatic ER required cytosol, ATP, Sar1 (a GTPase) and incubation at 37 degrees C. Proteinase K treatment did not degrade the VTV cargo protein, apoB100 (apolipoprotein 100), indicating that VTVs were sealed. Immunoblots showed that VTV concentrated apoB100, Sar1 and rSec22b, and excluded albumin and calnexin. VTVs were shown to fuse with cis-Golgi and delivered their cargo to the Golgi lumen, as determined by in vitro fusion, and acquired endoglycosidase H resistance. These results suggest that a new ER-derived transport vesicle (VTV) has been identified and characterized which transports nascent VLDL from the hepatic ER to the Golgi.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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VLDL exits from the endoplasmic reticulum in a specialized vesicle, the VLDL transport vesicle, in rat primary hepatocytes

Siddiqi

2008

Biochemical Journal

163

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“…Although the exact mechanism of apoB‐lipoprotein assembly is still undefined, it is believed that MTP transfers neutral lipids onto nascent apoB, while it is cotranslationally translocated into the endoplasmic reticulum (ER) to form primordial lipoproteins 4‐6. These are subsequently lipidated by a second step “core‐expansion” involving fusion of primordial lipoproteins with apoB‐free triglyceride‐rich droplets to form mature lipoproteins 7‐9. MTP is also implied to be essential for the partitioning of triglyceride into the ER lumen 10‐13…”

mentioning

confidence: 99%

“…These are subsequently lipidated by a second step “core‐expansion” involving fusion of primordial lipoproteins with apoB‐free triglyceride‐rich droplets to form mature lipoproteins 7‐9. MTP is also implied to be essential for the partitioning of triglyceride into the ER lumen 10‐13…”

mentioning

confidence: 99%

Phospholipid transfer activity of microsomal triglyceride transfer protein produces apolipoprotein B and reduces hepatosteatosis while maintaining low plasma lipids in mice

et al. 2012

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SUMMARY Microsomal triglyceride transfer protein (MTP), essential for apoB-lipoprotein biosynthesis, evolved as a phospholipid transfer protein and acquired triglyceride transfer activity during a transition from invertebrates to vertebrates. But it is unknown whether MTP directly transfers lipids onto apoB in vivo and, if it does, whether both neutral and polar lipid transfer activities of MTP are critical for lipoprotein assembly. The molecular bases for differences in lipid transfer activities with respect to distinct domains in dMTP and hMTP are not obvious because both proteins have very similar primary, secondary and tertiary structures. We used an in vivo approach to delineate physiological significance of these distinct lipid transfer activities by expressing Drosophila (transfers phospholipids) and human MTP (transfers phospholipids and triglycerides) orthologs using adenoviruses in liver-specific MTP deficient (L-MTP−/−) mice that have low plasma and high hepatic lipids. Both orthologs improved plasma lipids but plasma triglycerides were lower in dMTP mice due to lower hepatic triglyceride and apoB production. Hepatosteatosis in L-MTP−/− mice was ameliorated to similar levels by both. Attenuation of hepatosteatosis upon dMTP expression pertained to enhanced β-oxidation with no changes in lipogenesis. Phospholipid transfer activity of MTP promoted biogenesis of both apoB48 and apoB100-containing VLDL in addition to a phospholipid-rich apoB48-containing HDL-size particle. Triglyceride transfer activity augmented the biosynthesis of triglyceride-rich lipoproteins by increasing the formation of these particles in the lumen of the endoplasmic reticulum. Based on these findings, we posit that the selective inhibition of MTP triglyceride transfer activity might reduce hyperlipidemia while protecting liver from excess lipid accumulation.

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Acute suppression of VLDL1 secretion rate by insulin is associated with hepatic fat content and insulin resistance

Adiels¹,

et al. 2007

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Subcellular Localization of “B” Apoprotein of Plasma Lipoproteins in Rat Liver

Cited by 19 publications

References 22 publications

VLDL exits from the endoplasmic reticulum in a specialized vesicle, the VLDL transport vesicle, in rat primary hepatocytes

VLDL exits from the endoplasmic reticulum in a specialized vesicle, the VLDL transport vesicle, in rat primary hepatocytes

Phospholipid transfer activity of microsomal triglyceride transfer protein produces apolipoprotein B and reduces hepatosteatosis while maintaining low plasma lipids in mice

Acute suppression of VLDL1 secretion rate by insulin is associated with hepatic fat content and insulin resistance

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