Intestinal and hepatic apolipoprotein B gene expression in abetalipoproteinemia

Black, Dennis D.; Hay, Robert J.; Rohwer-Nutter, Patricia; Ellinas, Herodotos; Stephens, Janet K.; Sherman, Helayne; Teng, Ba Bie; Whitington, Peter F.; Davidson, Nicholas O.

doi:10.1016/0016-5085(91)90033-h

Cited by 52 publications

(34 citation statements)

References 45 publications

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“…Considered together, these studies provide a compelling argument that the liver and the intestine contribute nearly equally to the maintenance of normal plasma HDL levels. From the perspective of understanding abetalipoproteinemia, we found that the absence of MTP did not result in a compensatory upregulation of hepatic apo B mRNA levels, as had been suggested by several studies in humans (44)(45)(46). The absence of a change in Apob mRNA levels is in keeping with the fact that apo B mRNA levels typically change very little in response to a variety of other metabolic interventions (58).…”

Section: Figuresupporting

confidence: 77%

“…To address that hypothesis, we isolated primary hepatocytes from Mttp ∆/∆ and Mttp wt/wt mice and Normal apo B-100 mRNA levels in the livers of mice lacking hepatic Mttp gene expression. Several groups have reported elevated apo B mRNA levels in the tissues of humans with abetalipoproteinemia (44)(45)(46), raising the possibility of feedback upregulation of apo B synthesis in the setting of diminished lipoprotein secretion. To test whether hepatic MTP deficiency truly results in an upregulation of apo B mRNA levels, we measured Apob mRNA levels in Mttp ∆/∆ and Mttp wt/wt mice with a β-actin-controlled RPA.…”

Section: Generating and Characterizing Mice With A Floxed Mttp Allelementioning

confidence: 99%

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Analysis of the role of microsomal triglyceride transfer protein in the liver of tissue-specific knockout mice

Raabe¹,

Véniant²,

Sullivan³

et al. 1999

J. Clin. Invest.

403

384

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A deficiency in microsomal triglyceride transfer protein (MTP) causes the human lipoprotein deficiency syndrome abetalipoproteinemia. However, the role of MTP in the assembly and secretion of VLDL in the liver is not precisely understood. It is not clear, for instance, whether MTP is required to move the bulk of triglycerides into the lumen of the endoplasmic reticulum (ER) during the assembly of VLDL particles. To define MTP's role in hepatic lipoprotein assembly, we recently knocked out the mouse MTP gene (Mttp). Unfortunately, achieving our objective was thwarted by a lethal embryonic phenotype. In this study, we produced mice harboring a "floxed" Mttp allele and then used Cre-mediated recombination to generate liver-specific Mttp knockout mice. Inactivating the Mttp gene in the liver caused a striking reduction in VLDL triglycerides and large reductions in both VLDL/LDL and HDL cholesterol levels. The Mttp inactivation lowered apo B-100 levels in the plasma by >95% but reduced plasma apo B-48 levels by only ∼20%. Histologic studies in liver-specific knockout mice revealed moderate hepatic steatosis. Ultrastructural studies of wild-type mouse livers revealed numerous VLDL-sized lipid-staining particles within membrane-bound compartments of the secretory pathway (ER and Golgi apparatus) and few cytosolic lipid droplets. In contrast, VLDL-sized lipid-staining particles were not observed in MTPdeficient hepatocytes, either in the ER or in the Golgi apparatus, and there were numerous cytosolic fat droplets. We conclude that MTP is essential for transferring the bulk of triglycerides into the lumen of the ER for VLDL assembly and is required for the secretion of apo B-100 from the liver.J. Clin. Invest. 103:1287-1298(1999 to play an important role in this first "apo B lipidation" step (1,21,25). The existence of apo B in the rough ER of hepatocytes has been documented by immunoelectron microscopy (16). However, the lipidated apo B particles cannot be seen in the rough ER by routine electron microscopy, even when the thin sections are stained for lipids, because those particles are too small (< 150 Å in diameter) and lipid poor to be resolved by this technique. In a second step, the lipidated apo B molecule is thought to acquire the bulk of its core lipids by fusing with a large, VLDL-sized, apo B-free triglyceride particle (a "second-step" particle) (17,23). The existence of the secondstep triglyceride particles within a special compartment of the smooth ER has been supported by 2 different electron microscopic studies (16,23). Biochemical studies of VLDL assembly have also supported the concept that the bulk of neutral lipids are added to apo B in a second step after its translation is complete (1, 24).The role, if any, of MTP in the formation of second-step lipid particles is unclear. In fact, this issue has recently been highlighted as one of the fundamental problems in understanding MTP and lipoprotein assembly (15,26). In recent years, several groups have tried to address this issue by performing metabolic la...

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Section: Figuresupporting

confidence: 77%

Section: Generating and Characterizing Mice With A Floxed Mttp Allelementioning

confidence: 99%

Analysis of the role of microsomal triglyceride transfer protein in the liver of tissue-specific knockout mice

Raabe¹,

Véniant²,

Sullivan³

et al. 1999

J. Clin. Invest.

403

384

View full text Add to dashboard Cite

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“…Hepatic steatosis has not been reported uniformly (although it is frequent), and hepatic fi brosis or cirrhosis has been reported in a few cases ( 18,19 ). We report here an atypical case of ABL presenting in childhood with severe liver injury, hypocholesterolemia associated with a low (but not absent) levels of plasma ApoB, and a subnormal level of plasma vitamin E. Furthermore, the patient exhibited normal development into adulthood.…”

Section: Protein Expressionmentioning

confidence: 78%

Molecular and functional analysis of two new MTTP gene mutations in an atypical case of abetalipoproteinemia

Filippo

Crehalet

Samson-Bouma

et al. 2012

Journal of Lipid Research

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“…Our re-cently demonstrated that ApoA-I binds in a specific, saturable, and concentration-dependent manner to fisults are similar to those of a previous report. 16 In animal models without liver disease, it has been shown bronectin, an extracellular matrix component. 28 Therefore, we suggest that posttranscriptional mechanisms, that ApoB mRNA abundance does not correlate with serum ApoB concentration or ApoB production.…”

Section: Discussionmentioning

confidence: 99%

Quantification of apolipoprotein A-I and B messenger RNA in heavy drinkers according to liver disease

Mathurin

Vidaud

et al. 1996

Hepatology

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It has previously been shown that, in heavy drinkers, Apolipoprotein A-I (ApoA-I), a major component of serum apolipoprotein A-I (ApoA-I) levels are closely re-high-density lipoprotein, is synthesized in equal prolated to the degree of liver injury: they are at a maximum portions by the liver and the intestine. Like the level in patients with steatosis, begin to decrease in patients of high-density lipoprotein the level of ApoA-I has been with fibrosis, and reach a minimum in patients with se-shown to be inversely correlated with the development vere cirrhosis. In contrast with serum ApoA-I variations, of coronary artery disease. Variations in serum ApoAserum apolipoprotein B (ApoB) levels are stable. The as-I are also correlated with alcohol consumption and the with fibrosis or nonsevere cirrhosis (group II), and 4 ApoA-I is increased in alcoholic patients with normal with severe cirrhosis (group III). For ApoA-I, group I liver or steatosis. 5-8 However, serum ApoA-I is dehad higher serum levels (208.4 { 37.6 mg/dL mean { SE) creased in alcoholic patients with liver fibrosis indeand mRNA levels (0.51 { 0.12) than group II (serum 116 pendently of nutritional parameters. 1,2 { 19 mg/dL, P õ .01, mRNA 0.40 { 0.11, P õ .09) or groupWe and others have validated a simple index referred III (serum 56.5 { 28.6 mg/dL, P õ .01, mRNA 0.27 { .02, to as PGA, which includes a specific test for severe liver P Å .008). For ApoB, the three groups had similar serum disease (prothrombin time), a sensitive test for alcohol- There was a significant correlation between serum and index varied from 0 to 12. When PGA was°2, the mRNA levels of ApoA-I (r Å .65, P Å .003) but no correla-probability of cirrhosis was 0% and the probability of tion between serum and mRNA levels of ApoB (r Å .19, normal liver or minimal changes 83%. Conversely, NS). We suggest that (1) steatosis is associated with in-when PGA was ¢9, the probability of cirrhosis was creased ApoAI mRNA; (2) fibrosis is associated with de-86%.

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Intestinal and hepatic apolipoprotein B gene expression in abetalipoproteinemia

Cited by 52 publications

References 45 publications

Analysis of the role of microsomal triglyceride transfer protein in the liver of tissue-specific knockout mice

Analysis of the role of microsomal triglyceride transfer protein in the liver of tissue-specific knockout mice

Molecular and functional analysis of two new MTTP gene mutations in an atypical case of abetalipoproteinemia

Quantification of apolipoprotein A-I and B messenger RNA in heavy drinkers according to liver disease

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