Phospholipid Transfer Protein Plays a Major Role in the Initiation of Apolipoprotein B-containing Lipoprotein Assembly in Mouse Primary Hepatocytes

Manchekar, Medha; Liu, Yanwen; Sun, Zhihuan; Richardson, Patricia A.; Dashti, Nassrin

doi:10.1074/jbc.m114.602748

Cited by 24 publications

(18 citation statements)

References 46 publications

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“…Studies have also shown that PLTP deficiency reduces the secretion of the N-terminal 1000 residues (apoB:1000) of apoB. These studies suggest that PLTP may also play a role in the first step of lipoprotein assembly (59). It is likely that PLTP plays an auxiliary role in both the steps, as both steps depend on the availability of phospholipids.…”

Section: Phospholipid Transfer Proteinmentioning

confidence: 93%

Lipid transfer proteins in the assembly of apoB-containing lipoproteins

Sirwi

Hussain

2018

Journal of Lipid Research

112

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Running Title: Lipid transfer proteins and lipoprotein assemblyAbbreviations used: ARF1, ADP ribosylation factor 1; AUP1, ancient ubiquitous protein 1; Blps, apoB-containing lipoproteins; CIDEB, cell death-inducing DFF45-like effector B; COPII, coat protein complex II; cLDs, cytoplasmic lipid droplets; ER, endoplasmic reticulum; MTTP, microsomal triglyceride transfer protein; PLTP, phospholipid transfer protein AbstractA better understanding of intracellular lipoprotein assembly may help identify proteins with important roles in lipid disorders. ApoB-containing lipoproteins are macromolecular lipid and protein micelles that act as specialized transport vehicles for hydrophobic lipids. They are assembled predominantly in enterocytes and hepatocytes to transport dietary and endogenous fat, respectively, to different tissues. Assembly occurs in the endoplasmic reticulum and is dependent on lipid re-synthesis in the endoplasmic reticulum and on a chaperone, namely microsomal triglyceride transfer protein. Precursors for lipid synthesis are obtained from extracellular sources and from cytoplasmic lipid droplets. Microsomal triglyceride transfer protein is the major and essential lipid transfer protein that transfers phospholipids and triacylglycerols to nascent apoB for the assembly of lipoproteins. Assembly is aided by cell death-inducing DFF45-like effector B and by phospholipid transfer protein, which may facilitate additional deposition of triacylglycerols and phospholipids, respectively, to apoB. Here, we summarize the current understanding of the different steps in the assembly of apoB-containing lipoproteins and discuss the role of lipid transfer proteins in these steps to help identify new clinical targets for lipid-associated disorders, such as heart disease. IntroductionHydrophobic lipids serve as a source of energy, structural components for membranes, and precursors of hormones. Owing to their hydrophobicity, lipids require special means of transport in the aqueous milieu of the human body. Three different modes of lipid transport are known. First, micellar solubilization of lipids in the intestinal lumen facilitates hydrolysis of dietary lipids in the lumen and uptake by enterocytes. Second, transport of lipids bound to proteins, e.g., albumin, occurs in the circulation. Third, the most efficient process of transporting lipids in bulk through an aqueous milieu of the blood circulation is via special protein-lipid macromolecular micelles called lipoproteins, which consist of a hydrophilic surface and a hydrophobic core. The hydrophilic surface is a monolayer of phospholipids that also contains free cholesterol and other exchangeable proteins called apolipoproteins. The lipoprotein core is devoid of proteins and consists of hydrophobic lipids, such as triacylglycerols, cholesteryl esters, vitamin E, and vitamin A. A major protein constituent of these lipoproteins is apoB, which is a very hydrophobic scaffolding protein. The apoB-containing lipoproteins (B-lps) are large spherical particles and are classif...

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Section: Phospholipid Transfer Proteinmentioning

confidence: 93%

Lipid transfer proteins in the assembly of apoB-containing lipoproteins

Sirwi

Hussain

2018

Journal of Lipid Research

112

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“…We summarized our finding in Figure E. We believe the following: (1) PLTP is involved in apoB particle lipidation and secretion in the liver; without PLTP, VLDL production is greatly reduced . (2) Profurin could regulate PLTP through promoting apoB particle intracellular degradation.…”

Section: Discussionmentioning

confidence: 81%

“…Okazaki et al reported that, in concert with the increase in triglyceride synthesis, the increased PLTP activity permits triglyceride incorporation into large VLDLs . Dashti and colleagues found that PLTP played a major role in the initiation of apoB‐containing particle assembly in mouse primary hepatocytes . More important, human genome‐wide association studies and many others have shown that human PLTP levels are positively associated with plasma triglyceride and apoB levels .…”

Section: Discussionmentioning

confidence: 99%

“…45 Dashti and colleagues found that PLTP played a major role in the initiation of apoB-containing particle assembly in mouse primary hepatocytes. 37 More important, human genome-wide association studies and many others have shown that human PLTP levels are positively associated with plasma triglyceride and apoB levels. 7,46 We reason that PLTP activity is involved in promoting VLDL lipidation, because PLTP activity and triglyceride enrichment are 2 factors regulating PLTP-mediated HDL enlargement, 47,48 a process similar to VLDL lipidation.…”

Section: Discussionmentioning

confidence: 99%

“…However, profurin had no effect on cholesteryl ester transfer protein, a protein in the same gene as PLTP ( Figure 4B). We next evaluated profurin expression on apoB secretion, a PLTP involved process 20,37,38 ; we found that AdV-profurin treated Huh7 cells reduced cell PLTP activity and apoB secretion ( Figure 4C and 4D). We then hypothesized that profurin promotes the intracellular degradation of PLTP.…”

Section: Profurin Expression Promotes Intracellular Pltp Degradationmentioning

confidence: 99%

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Prodomain of Furin Promotes Phospholipid Transfer Protein Proteasomal Degradation in Hepatocytes

Xia

Jiang

et al. 2018

JAHA

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BackgroundPhospholipid transfer protein (PLTP) is one of the major modulators of lipoprotein metabolism and atherosclerosis development; however, little is known about the regulation of PLTP. The effect of hepatic prodomain of furin (profurin) expression on PLTP processing and function is investigated.Methods and ResultsWe used adenovirus expressing profurin in mouse liver to evaluate PLTP activity, mass, and plasma lipid levels. We coexpressed PLTP and profurin in human hepatoma cell line cells and studied their interaction. We found profurin expression significantly reduced plasma lipids, plasma PLTP activity, and mass in all tested mouse models, compared with controls. Moreover, the expression of profurin dramatically reduced liver PLTP activity and protein level. We further explored the mechanism using in vivo and ex vivo approaches. We found that profurin can interact with intracellular PLTP and promote its ubiquitination and proteasomal degradation, resulting in less PLTP secretion from the hepatocytes. Furin does not cleave PLTP; instead, it forms a complex with PLTP, likely through its prodomain.ConclusionsOur study reveals that hepatic PLTP protein is targeted for proteasomal degradation by profurin expression, which could be a novel posttranslational mechanism underlying PLTP regulation.

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Impact of Phospholipid Transfer Protein in Lipid Metabolism and Cardiovascular Diseases

Jiang

2020

Advances in Experimental Medicine and Biology

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Phospholipid Transfer Protein Plays a Major Role in the Initiation of Apolipoprotein B-containing Lipoprotein Assembly in Mouse Primary Hepatocytes

Cited by 24 publications

References 46 publications

Lipid transfer proteins in the assembly of apoB-containing lipoproteins

Lipid transfer proteins in the assembly of apoB-containing lipoproteins

Prodomain of Furin Promotes Phospholipid Transfer Protein Proteasomal Degradation in Hepatocytes

Impact of Phospholipid Transfer Protein in Lipid Metabolism and Cardiovascular Diseases

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