The Activity of Microsomal Triglyceride Transfer Protein Is Essential for Accumulation of Triglyceride within Microsomes in McA-RH7777 Cells

Wang, Yuwei; Tran, Khai; Yao, Zemin

doi:10.1074/jbc.274.39.27793

Cited by 128 publications

(154 citation statements)

References 41 publications

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“…The total plasma cholesterol levels were quite insensitive to the effects of the Mttp knockout mutation, although the FPLC fractionation studies did uncover ϳ20% reductions in low density lipoprotein cholesterol levels at each level of apoB synthesis. A single copy of the Mttp knockout allele had no detectable effect on plasma triglyceride levels, a somewhat surprising result in light of recent studies that have shown that hepatic MTP plays a crucial role in triglyceride secretion (7,33). We do not understand why the Mttp mutation failed to reduce the plasma triglyceride levels.…”

Section: Effects Of Mtp Deficiency On Apob Secretionmentioning

confidence: 68%

A Deficiency of Microsomal Triglyceride Transfer Protein Reduces Apolipoprotein B Secretion

Leung¹,

Véniant²,

Kim³

et al. 2000

Journal of Biological Chemistry

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Microsomal triglyceride transfer protein (MTP) transfers lipids to apolipoprotein B (apoB) within the endoplasmic reticulum, a process that involves direct interactions between apoB and the large subunit of MTP. Recent studies with heterozygous MTP knockout mice have suggested that half-normal levels of MTP in the liver reduce apoB secretion. We hypothesized that reduced apoB secretion in the setting of half-normal MTP levels might be caused by a reduced MTP:apoB ratio in the endoplasmic reticulum, which would reduce the number of apoB-MTP interactions. If this hypothesis were true, half-normal levels of MTP might have little impact on lipoprotein secretion in the setting of halfnormal levels of apoB synthesis (since the ratio of MTP to apoB would not be abnormally low) and might cause an exaggerated reduction in lipoprotein secretion in the setting of apoB overexpression (since the MTP:apoB ratio would be even lower). To test this hypothesis, we examined the effects of heterozygous MTP deficiency on apoB metabolism in the setting of normal levels of apoB synthesis, half-normal levels of apoB synthesis (heterozygous Apob deficiency), and increased levels of apoB synthesis (transgenic overexpression of human apoB). Contrary to our expectations, half-normal levels of MTP reduced the plasma apoB100 levels to the same extent (ϳ25-35%) at each level of apoB synthesis. In addition, apoB secretion from primary hepatocytes was reduced to a comparable extent at each level of apoB synthesis. Thus, these results indicate that the concentration of MTP within the endoplasmic reticulum rather than the MTP:apoB ratio is the critical determinant of lipoprotein secretion. Finally, we found that heterozygosity for an apoB knockout mutation lowered plasma apoB100 levels more than heterozygosity for an MTP knockout allele. Consistent with that result, hepatic triglyceride accumulation was greater in heterozygous apoB knockout mice than in heterozygous MTP knockout mice. Microsomal triglyceride transfer protein (MTP)1 is expressed at high levels in the absorptive enterocytes of the intestine and hepatocytes, at moderate levels in the visceral endoderm of the yolk sac during embryonic development, and at relatively low levels in kidney and cardiac muscle (1-4). In each of these tissues, MTP plays a key role in the assembly and secretion of apoB-containing lipoproteins (1, 3, 5). MTP is located within the lumen of the endoplasmic reticulum (ER) and is thought to transfer lipids to apoB as that molecule is translated, allowing apoB to assume a proper conformation for forming a spherical lipoprotein with a neutral lipid core (6). In the absence of MTP, triglyceride-rich, apoB-containing lipoproteins cannot be assembled or secreted (3, 6, 7). The mechanism of MTP action has attracted considerable scrutiny. Of note, several lines of evidence have suggested that the assembly of lipoproteins involves a direct interaction between MTP and apoB. First, Wu et al. (8) demonstrated that apoB can be immunoprecipitated from the microsomes of cult...

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Section: Effects Of Mtp Deficiency On Apob Secretionmentioning

confidence: 68%

A Deficiency of Microsomal Triglyceride Transfer Protein Reduces Apolipoprotein B Secretion

Leung¹,

Véniant²,

Kim³

et al. 2000

Journal of Biological Chemistry

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“…[28][29][30][31] Subjects with mutations of the MTP gene also can have hepatic steatosis, 32,33 and similar effects occur in animals whose MTP gene is inactivated. 34,35 Finally, the hepatitis C virus core protein did not modify in vivo fatty acid oxidation but impaired MTP activity in transgenic mice, which developed hepatic steatosis.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Microsomal Triglyceride Transfer Protein: Another Mechanism for Drug–Induced Steatosis in Mice

2003

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Although many steatogenic drugs inhibit mitochondrial fatty acid ␤-oxidation, limited information is available on possible effects on hepatic lipoprotein secretion. In the endoplasmic reticulum (ER) lumen, microsomal triglyceride transfer protein (MTP) lipidates apolipoprotein B (Apo B), to form triglyceride (TG)-rich very low density lipoprotein (VLDL) particles, which follow vesicular flow to the plasma membrane to be secreted, whereas incompletely lipidated Apo B particles are partly degraded. We studied hepatic MTP activity, the lipoproteins present in the ER lumen, and hepatic lipoprotein secretion 4 hours after administration of a single dose of amineptine (1 mmol/kg), amiodarone (1 mmol/kg), doxycycline (0.25 mmol/kg), tetracycline (0.25 mmol/kg), tianeptine (0.5 mmol/ kg), or pirprofen (2 mmol/kg) in mice. These various doses have been shown previously to markedly inhibit fatty acid oxidation after a single dose, and to trigger steatosis either after repeated doses (doxycycline) or a single dose (other compounds) in mice. In the present study, amineptine, amiodarone, pirprofen, tetracycline, and tianeptine, but not doxycycline, inhibited MTP activity in vitro, decreased ex vivo MTP activity in the hepatic homogenate of treated mice, decreased TG in the luminal VLDL fraction of hepatic microsomes of treated mice, and decreased in vivo hepatic lipoprotein secretion (TG and Apo B). In conclusion, several steatogenic drugs inhibit not only mitochondrial ␤-oxidation, as previously shown, but also MTP activity, Apo B lipidation into TG-rich VLDL particles, and hepatic lipoprotein secretion. Drugs with these dual effects may be more steatogenic than drugs acting only on ␤-oxidation or only MTP. (HEPATOLOGY 2003;38:133-140.)

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“…Hence, in insects, extensive trafficking of lipids into the secretory pathway would be counterproductive to the pathway of cytosolic lipid mobilization. Together, these findings raise the possibility that invertebrate MTPs have evolved only those functions required for first step particle formation but not steps associated with the trafficking of bulk lipid into the secretory pathway, an important prerequisite for second step expansion of apoB-containing particles into mature VLDL and chylomicrons (23)(24)(25). This may explain the low lipid transfer activity associated with the Drosophila MTP ortholog, in vitro.…”

Section: Cg9342 Lacks a Hydrophobic Peptide Critical For Vertebrate Mmentioning

confidence: 97%

“…In addition, we observed functional and structural differences between CG9342 and human MTP, possibly reflecting known differences in intracellular and extracellular aspects of vertebrate and invertebrate lipid transport and metabolism. The identification of invertebrate orthologs of human MTP may enable structural and functional dissection of the multiple roles of human MTP in apoB assembly as well as apoB-independent effects on intracellular lipid trafficking (23)(24)(25) (26) as implemented by the SignalIP V2.0 server on the web. The amino terminus of mature human MTP was based on data reported by Shoulders et al (27).…”

mentioning

confidence: 99%

A Drosophila Microsomal Triglyceride Transfer Protein Homolog Promotes the Assembly and Secretion of Human Apolipoprotein B

Sellers

Athar

et al. 2003

Journal of Biological Chemistry

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The assembly and secretion of triglyceride-rich lipoproteins in vertebrates requires apolipoprotein B (apoB) and the endoplasmic reticulum-localized cofactor, microsomal triglyceride transfer protein (MTP). Invertebrates, particularly insects, transport the majority of their neutral and polar lipids in lipophorins; however, the assembly of lipophorin precursor particles was presumed to be MTP-independent. A Drosophila melanogaster expressed gene sequence (CG9342), displaying 23% identity with human MTP, was recently identified. When coexpressed in COS cells, CG9342 promoted the assembly and secretion of apoB34 and apoB41 (N-terminal 34 and 41% of human apoB). The apoB34-containing particles assembled by human MTP and CG9342 displayed similar peak densities of ϳ1.169 g/ml and similar lipid compositions. However, CG9342 displayed differential sensitivities to two inhibitors of human MTP and low vesicle-based lipid transfer activity, in vitro. In addition, important predicted structural distinctions exist between the human and Drosophila proteins suggesting overlapping but not identical functional roles. We conclude that CG9342 and human MTP are orthologs that share only a subset of functions, consistent with known differences in intracellular and extracellular aspects of vertebrate and invertebrate lipid transport and metabolism.

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The Activity of Microsomal Triglyceride Transfer Protein Is Essential for Accumulation of Triglyceride within Microsomes in McA-RH7777 Cells

Cited by 128 publications

References 41 publications

A Deficiency of Microsomal Triglyceride Transfer Protein Reduces Apolipoprotein B Secretion

A Deficiency of Microsomal Triglyceride Transfer Protein Reduces Apolipoprotein B Secretion

Inhibition of Microsomal Triglyceride Transfer Protein: Another Mechanism for Drug–Induced Steatosis in Mice

A Drosophila Microsomal Triglyceride Transfer Protein Homolog Promotes the Assembly and Secretion of Human Apolipoprotein B

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