Pathology of chronic vitamin E deficiency in fatal familial intrahepatic cholestasis (Byler disease)

Saito, Ken; Matsumoto, Saburo; Yokoyama, Takeshi; Okaniwa, Mariko; Kamoshita, Shigehiko

doi:10.1007/bf00431391

“…In the same mice we used in this study, deletion of MTP did not, by itself, cause liver dysfunction, but it did increase susceptibility to toxin-induced liver injury (48). This increased susceptibility may be caused by impaired transport of essential lipid nutrients, such as vitamin E (8,55,56). The previous studies suggesting that MTP inhibitors corrected the marked hypercholesterolemia in Watanabe-heritable hyperlipidemic rabbits (13) provided support suggesting a possible alternative treatment for homozygous familial hypercholesterolemia, a lethal disorder corrected by liver transplantation (15).…”

Section: Discussionmentioning

confidence: 87%

“…1D). Surprisingly, loss of MTP expression was by guest, on August 29, 2018 www.jlr.org Downloaded from associated with a nearly complete absence of apoB-100 in hepatic microsomes. The amount of apoB-48 was unaffected (Fig.…”

Section: Effects Of Disrupting Mttp In the Livermentioning

confidence: 91%

Blocking microsomal triglyceride transfer protein interferes with apoB secretion without causing retention or stress in the ER

Liao

¹

,

Hui

²

,

Young

³

et al. 2003

Journal of Lipid Research

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Microsomal triglyceride transfer protein (MTP)is an intraluminal protein in the endoplasmic reticulum (ER) that is essential for the assembly of apolipoprotein B (apoB)-containing lipoproteins. In this study, we examine how the livers of mice respond to two distinct methods of blocking MTP function: Cre -mediated disruption of the gene for MTP and chemical inhibition of MTP activity. Blocking MTP significantly reduced plasma levels of triglycerides, cholesterol, and apoB-containing lipoproteins in both wild-type C57BL/6 and LDL receptor-deficient mice. While treating LDL receptor-deficient mice with an MTP inhibitor for 7 days lowered plasma lipids to control levels, liver triglyceride levels were increased by only 4-fold. Plasma levels of apoB-100 and apoB-48 fell by Ͼ 90% and 65%, respectively, but neither apoB isoform accumulated in hepatic microsomes. Surprisingly, loss of MTP expression was associated with a nearly complete absence of apoB-100 in hepatic microsomes. Levels of microsomal luminal chaperone proteins [e.g., protein disulfide isomerase, glucoseregulated protein 78 (GRP78), and GRP94] and cytosolic heat shock proteins (HSPs) (e.g., HSP60, HSC, HSP70, and HSP90) were unaffected by MTP inhibition. These findings show that the liver responds rapidly to inhibition of MTP by degrading apoB and preventing its accumulation in the ER.The rapid degradation of secretion-incompetent apoB in the ER may block the induction of proteins associated with unfolded protein and heat shock responses. VLDLs produced by the liver are the major source of LDLs in the plasma, which are causally related to the development of atherosclerotic cardiovascular disease (1). The importance of the hepatic secretion of apolipoprotein B (apoB) in cardiovascular disease was recognized in early studies of abetalipoproteinemic patients, who lack the ability to secrete apoB-containing lipoproteins (2) and are markedly resistant to cardiovascular disease (3). Subsequent studies showed that specific mutations in the microsomal triglyceride transfer protein (MTP) gene are responsible for abetalipoproteinemia (4,5). MTP exists in a functional complex with protein disulfide isomerase (PDI) (6, 7). The loss of MTP function blocks the secretion of apoB-containing lipoproteins from both the liver and the intestine (5). Apart from neuropathy, which can be prevented by vitamin E supplements (8) and moderate steatosis in enterocytes and hepatocytes, abetalipoproteinemia is not usually associated with liver failure or cirrhosis (3). The absence of severe symptoms has suggested that inactivation of MTP might be a useful strategy for combating hyperlipidemia and cardiovascular disease.Several chemical inhibitors of the lipid transfer activity of MTP have been developed (9-12). Many of these inhibitors lower plasma lipid levels in animal models (11-13). Especially encouraging results were obtained in Watanabe-heritable hyperlipidemic rabbits, a model of homozygous familial hypercholesterolemia (13). Administration of an MTP inhibitor to Watan...

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“…Many cases were documented as case reports or in small series. To date, in excess of 130 splenic hamartomas have been documented in the English literature 1 –63 . Overall, hamartomas were detected over a wide age range (11 months to 86 years) and with a mean age of 47 years at presentation.…”

Section: Discussionmentioning

confidence: 99%

Splenic Vascular Lesions: Unusual Features and a Review of the Literature

Lam¹,

Yip²,

Peh

³

1999

Aust. N.Z. J. Surg.

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Hamartoma and peliosis are uncommon splenic lesions. Approximately 120 splenic hamartomas and 40 splenic peliosis have been reported in the English literature. In the present study, a unique case of multiple splenic hamartomas with peliosis was reported. The splenic lesions were incidental findings in a 36-year-old man with ruptured sarcomatoid renal cell carcinoma. They were diagnosed clinically as metastatic renal cell carcinoma. On pathological examination, peliosis was noted in the splenic hamartomas as well as in the splenic parenchyma. In addition, the clinicopathological features of five other splenic hamartomas (including one giant hamartoma) noted in our department were presented. A re-evaluation of the features of the splenic hamartomas documented in the English literature was also done.

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“…at Carleton Univ -OCUL, on June 17, 2015 www.jlr.org Downloaded from cumulate in hepatic ER. Our findings may also explain why blocking the secretion of apoB-containing lipoproteins by the liver in mice is not associated with the inflammatory responses associated with the accumulation of secretion-incompetent protein in the secretory pathway (unfolded-protein and heat shock responses) (38)(39)(40).…”

Section: Discussionmentioning

confidence: 99%

Anosognosia and the intracarotid amobarbital procedure (Wada test)

Mw¹,

Kj²,

Me³

et al. 1994

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Microsomal triglyceride transfer protein (MTP)is an intraluminal protein in the endoplasmic reticulum (ER) that is essential for the assembly of apolipoprotein B (apoB)-containing lipoproteins. In this study, we examine how the livers of mice respond to two distinct methods of blocking MTP function: Cre -mediated disruption of the gene for MTP and chemical inhibition of MTP activity. Blocking MTP significantly reduced plasma levels of triglycerides, cholesterol, and apoB-containing lipoproteins in both wild-type C57BL/6 and LDL receptor-deficient mice. While treating LDL receptor-deficient mice with an MTP inhibitor for 7 days lowered plasma lipids to control levels, liver triglyceride levels were increased by only 4-fold. Plasma levels of apoB-100 and apoB-48 fell by Ͼ 90% and 65%, respectively, but neither apoB isoform accumulated in hepatic microsomes. Surprisingly, loss of MTP expression was associated with a nearly complete absence of apoB-100 in hepatic microsomes. Levels of microsomal luminal chaperone proteins [e.g., protein disulfide isomerase, glucoseregulated protein 78 (GRP78), and GRP94] and cytosolic heat shock proteins (HSPs) (e.g., HSP60, HSC, HSP70, and HSP90) were unaffected by MTP inhibition. These findings show that the liver responds rapidly to inhibition of MTP by degrading apoB and preventing its accumulation in the ER.The rapid degradation of secretion-incompetent apoB in the ER may block the induction of proteins associated with unfolded protein and heat shock responses. -Liao, W., T. Y. Hui, S. G. Young, and R. Davis. Blocking microsomal triglyceride transfer protein interferes with apoB secretion without causing retention or stress in the ER. J. Lipid Res. 2003. 44: 978-985.Supplementary key words apolipoprotein B • endoplasmic reticulum • hyperlipidemia • liver • inflammation • unfolded protein response Abbreviations: ALLN, acetylated leucine, leucine, norleucal; ER, endoplasmic reticulum; GRP, glucose-regulated protein; HSP, heat shock protein; MTP, microsomal triglyceride transfer protein; PDI, protein disulfide isomerase.

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Pathology of chronic vitamin E deficiency in fatal familial intrahepatic cholestasis (Byler disease)

Cited by 27 publications

References 29 publications

Blocking microsomal triglyceride transfer protein interferes with apoB secretion without causing retention or stress in the ER

Blocking microsomal triglyceride transfer protein interferes with apoB secretion without causing retention or stress in the ER

Splenic Vascular Lesions: Unusual Features and a Review of the Literature

Anosognosia and the intracarotid amobarbital procedure (Wada test)

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