An MTP Inhibitor That Normalizes Atherogenic Lipoprotein Levels in WHHL Rabbits

Wetterau, John R.; Gregg, Richard E.; Harrity, Thomas; Arbeeny, Cynthia M.; Cap, Michael; Connolly, Fergal; Chu, Ching-Hsuen; George, R.J.; Gordon, David; Jamil, Haris; Jolibois, Kern G.; Kunselman, Lori; Lan, Shih-Jung; Maccagnan, T J; Ricci, Beverly; Yan, Mujing; Young, Douglas; Chen, Ying; Fryszman, Olga M.; Logan, Janette V. H.; Musial, Christa M.; Poss, Michael A.; Robl, Jeffrey A.; Simpkins, Ligaya M.; Slusarchyk, William A.; Sulsky, Richard; Taunk, Prakash; Magnin, David R.; Tino, Joseph A.; Lawrence, R. Michael; Dickson, John K.; Biller, Scott A.

doi:10.1126/science.282.5389.751

Cited by 260 publications

(160 citation statements)

References 13 publications

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“…Filters were exposed for 5-30 s. secretion of VLDL is required for HCV replication. For this purpose, we used an MTP inhibitor BMS-2101038 that blocks the secretion and accelerates the degradation of apoB by inhibiting MTP-mediated lipid transfer to apoB (25,26). Huh7-5A-GFP-6 cells were treated with various doses of the MTP inhibitor.…”

Section: Resultsmentioning

confidence: 99%

Hepatitis C virus production by human hepatocytes dependent on assembly and secretion of very low-density lipoproteins

Huang

Sun

Owen

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

489

440

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Hepatitis C virus (HCV) and triglyceride-rich very low-density lipoproteins (VLDLs) both are secreted uniquely by hepatocytes and circulate in blood in a complex. Here, we isolated from human hepatoma cells the membrane vesicles in which HCV replicates. These vesicles, which contain the HCV replication complex, are highly enriched in proteins required for VLDL assembly, including apolipoprotein B (apoB), apoE, and microsomal triglyceride transfer protein. In hepatoma cells that constitutively produce infectious HCV, HCV production is reduced by two agents that block VLDL assembly: an inhibitor of microsomal triglyceride transfer protein and siRNA directed against apoB. These results provide a possible explanation for the restriction of HCV production to the liver and suggest new cellular targets for treatment of HCV infection.apolipoprotein B ͉ microsomal triglyceride transfer protein

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Section: Resultsmentioning

confidence: 99%

Hepatitis C virus production by human hepatocytes dependent on assembly and secretion of very low-density lipoproteins

Huang

Sun

Owen

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

489

440

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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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“…For example, addition of oleic acid to hepatic cells in culture leads to increased TG synthesis within the cells and enhanced apoB secretion (17), whereas in rat hepatocytes this is not the case (22). MTP inhibitors prevent association of lipids with apoB, which abolishes apoB secretion (18). It is thought that these compounds change the availability of neutral lipids necessary for lipoprotein formation not only by their amounts but also by decreasing the efficiency of intracellular movement of the lipids.…”

mentioning

confidence: 99%

“…There are many published reports that indicate that apoB secretion is dramatically affected by exogenous compounds (17)(18)(19)(20)(21). For example, addition of oleic acid to hepatic cells in culture leads to increased TG synthesis within the cells and enhanced apoB secretion (17), whereas in rat hepatocytes this is not the case (22).…”

mentioning

confidence: 99%

Transmembrane Lipid Transfer Is Crucial for Providing Neutral Lipids during Very Low Density Lipoprotein Assembly in Endoplasmic Reticulum

Higashi

Itabe

Fukase

et al. 2003

Journal of Biological Chemistry

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Very low density lipoprotein (VLDL), a large particle containing apolipoprotein B (apoB) and large amounts of neutral lipids, is formed in the luminal space within the endoplasmic reticulum (ER) of hepatic cells. The assembly mechanism of VLDL particles is a tightly regulated process where apoB, associated with an insufficient amount of lipids, is selectively degraded intracellularly. In this study we found that treatment of HuH-7 human hepatoma cells with verapamil inhibited secretion of apoB-containing lipoprotein particles through increasing degradation of apoB. Addition of N-acetylleucyl-leucyl-norleucinal, an inhibitor of proteasome and other cysteinyl proteases that are responsible for apoB degradation, restored apoB recovery from verapamil-treated cells. De novo synthesis of lipids from [ 14 C]acetate was increased in the presence of verapamil, suggesting that verapamil decreases lipid availability for apoB thus leading to the secretion of apoB-containing lipoprotein. We prepared cytosolic fractions from cells preincubated with [ 14 C]acetate and used as a donor of radioactive lipids. When this cytosolic fraction was incubated with microsomes isolated separately, radioactive triglyceride (TG) accumulated in the luminal space of the microsomes. The transfer of radioactive TG from the cytosolic fraction to the microsomal lumen was inhibited in the presence of verapamil, suggesting that there is a verapamil-sensitive mechanism for TG transfer across ER membranes that is involved in formation of apoB-containing lipoprotein particles in ER. Verapamil showed no inhibitory effect on microsomal TG transfer protein, a well known lipid transfer protein in ER. We propose from these results that there is novel machinery for transmembrane movement of neutral lipids, which is involved in providing TG for apoB during VLDL assembly in ER.The liver plays a central role in lipoprotein metabolism through secretion of very low density lipoprotein (VLDL) 1 , which carries neutral lipids to all peripheral tissues. VLDL, a large particle containing apolipoprotein B (apoB) and various lipids, including triglyceride (TG), free cholesterol (FC), and cholesteryl ester (CE), is assembled in endoplasmic reticulum (ER) in hepatic cells. Mechanisms of VLDL particle formation are likely to be rigorously regulated, because association of lipids to apoB needs to occur cotranslationally, and poorly lipidated apoB-containing lipoprotein is degraded by proteasome or ER-resident proteases such as ER-60 prior to secretion (1-3). Thus it is thought that the association of lipids to apoB is a rate-limiting step for VLDL secretion, with regulation of this process controlled by as yet unknown mechanisms. One of the factors for this lipid transfer is microsomal triglyceride transfer protein (MTP), a lack of which was identified as the cause of abetalipoproteinemia, an autosomal recessive disease with total loss of apoB-containing lipoprotein in plasma (4, 5). MTP locates in the luminal space of ER by forming heterodimers with protein disulfide isom...

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An MTP Inhibitor That Normalizes Atherogenic Lipoprotein Levels in WHHL Rabbits

Cited by 260 publications

References 13 publications

Hepatitis C virus production by human hepatocytes dependent on assembly and secretion of very low-density lipoproteins

Hepatitis C virus production by human hepatocytes dependent on assembly and secretion of very low-density lipoproteins

Inhibition of microsomal triglyceride transfer protein: Another mechanism for drug-induced steatosis in mice

Transmembrane Lipid Transfer Is Crucial for Providing Neutral Lipids during Very Low Density Lipoprotein Assembly in Endoplasmic Reticulum

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