Hepatic peroxisomal abnormalities in abetalipoproteinemia

Collins, Janna C.; Scheinberg, I. Herbert; Giblin, Denis R.; Sternlieb, Irmin

doi:10.1016/0016-5085(89)90651-3

Cited by 41 publications

(31 citation statements)

References 11 publications

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“…The observation that some (54) [but not all (2,8,55)] abetalipoproteinemic patients develop liver disease implies that the response of the human liver to MTP inhibition may be influenced by genetic and environmental factors. 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).…”

Section: Discussionmentioning

confidence: 99%

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

Liao

Hui

Young

et al. 2003

Journal of Lipid Research

103

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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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Section: Discussionmentioning

confidence: 99%

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

Liao

Hui

Young

et al. 2003

Journal of Lipid Research

103

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“…Loss of CPT-I inhibition by malonyl-CoA could explain why b-oxidation can increase in type 2 diabetic states, despite high insulin and malonyl-CoA levels, which, normally would block the entry of long-chain fatty acids into mitochondria. Finally, another mechanism increasing fatty acid oxidation may be the proliferation and enlargement of hepatic peroxisomes in patients with a fatty liver [77,78]. An important upstream mediator of these diverse changes may be PPAR-a.…”

Section: High Glucose And/or Insulin Levels Induce Hepatic Lipogenesimentioning

confidence: 97%

NASH: a mitochondrial disease

Pessayre

Fromenty

2005

Journal of Hepatology

394

353

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“…Hepatic steatosis in other settings has been associated with the development of other pathologies, ranging from nonalcoholic steatohepatitis and cirrhosis to insulin resistance. 69 The complete MTP deficiency state, abetalipoproteinemia, is variably associated with some degree of hepatosteatosis [70][71][72][73][74] ; however, liver fibrosis is rare and has generally been observed in the setting of medium-chain triglyceride supplementation, [75][76][77][78] which has been implicated as a possible culprit contributing to progressive liver disease. 75,76 Patients with hypobetalipoproteinemia resulting from apoB mutations generally have increased hepatic fat but do not appear to progress to fibrotic liver disease.…”

Section: Increased Hepatic Fat and Long-term Hepatic Safety Are The Mmentioning

confidence: 99%