Targeted modification of the apolipoprotein B gene results in hypobetalipoproteinemia and developmental abnormalities in mice.

Homanics, Gregg E.; Smith, Terry J.; Zhang, Sunny H.; Lee, Denise; Young, Stephen G.; Maeda, Nobuyo

doi:10.1073/pnas.90.6.2389

Cited by 117 publications

(59 citation statements)

References 33 publications

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“…Kono et al [76] suggested recently that LDL particles carry the major portion of plasma α-TOH and that LDLR-mediated endocytosis contributes significantly to the uptake of α-TOH into cells [77] . However, studies performed on apolipoprotein B (Apob)-knockout mice and heritable hyperlipidemic Watanabe rabbits lacking the LDLR showed discrepancies in circulating α-TOH levels and tissue distribution, thus questioning the importance of LDL for α-TOH transport [78,79] . Cohn et al [79] therefore concluded that α-TOH in LDL can be taken up by tissues via LDLR but is also independent of this lipoprotein receptor.…”

Section: Vascular Transportmentioning

confidence: 99%

Complexity of vitamin E metabolism

Schmölz¹,

Birringer²,

Lorkowski³

et al. 2016

WJBC

178

138

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Bioavailability of vitamin E is influenced by several factors, most are highlighted in this review. While gender, age and genetic constitution influence vitamin E bioavailability but cannot be modified, life-style and intake of vitamin E can be. Numerous factors must be taken into account however, i.e. , when vitamin E is orally administrated, the food matrix may contain competing nutrients. The complex metabolic processes comprise intestinal absorption, vascular transport, hepatic sorting by intracellular binding proteins, such as the significant α-tocopherol-transfer protein, and hepatic metabolism. The coordinated changes involved in the hepatic metabolism of vitamin E provide an effective physiological pathway to protect tissues against the excessive accumulation of, in particular, non-α-tocopherol forms. Metabolism of vitamin E begins with one cycle of CYP4F2/CYP3A4-dependent ω-hydroxylation followed by five cycles of subsequent β-oxidation, and forms the water-soluble end-product carboxyethylhydroxychroman. All known hepatic metabolites can be conjugated and are excreted, depending on the length of their sidechain, either via urine or feces. The physiological handling of vitamin E underlies kinetics which vary between the different vitamin E forms. Here, saturation of the side-chain and also substitution of the chromanol ring system are important. Most of the metabolic reactions and processes that are involved with vitamin E are also shared by other fat soluble vitamins. Influencing interactions with other nutrients such as vitamin K or pharmaceuticals are also covered by this review. All these processes modulate the formation of vitamin E metabolites and their concentrations in tissues and body fluids. Differences in metabolism might be responsible for the discrepancies that have been observed in studies performed in vivo and in vitro using vitamin E as a REVIEW

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Section: Vascular Transportmentioning

confidence: 99%

Complexity of vitamin E metabolism

Schmölz¹,

Birringer²,

Lorkowski³

et al. 2016

WJBC

178

138

View full text Add to dashboard Cite

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mentioning

confidence: 99%

“…FHBL is defined by less than fifth percentile plasma levels of LDL-cholesterol and/or total apolipoprotein B (apoB), segregating in families as an autosomal dominant trait (15-17). The mean liver triglyceride content in apoBimpaired FHBL subjects is 3-to 5-fold greater than that of controls (18,19).In an attempt to understand the cellular/molecular bases of hypobetalipoproteinemia, several recombinant mice mimicking human FHBL have been produced (19)(20)(21)(22)(23)(24)(25). The resulting mice closely resemble their human counterparts with respect to the fatty liver phenotype.…”

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confidence: 99%

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In vivo MRS measurement of liver lipid levels in mice

Garbow

Lin

Sakata

et al. 2004

Journal of Lipid Research

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A magnetic resonance spectroscopy (MRS) procedure for in vivo measurement of lipid levels in mouse liver is described and validated. The method uses respiratory-gated, localized spectroscopy to collect proton spectra from voxels within the mouse liver. Bayesian probability theory analysis of these spectra allows the relative intensities of the lipid and water resonances within the liver to be accurately measured. All spectral data were corrected for measured spin-spin relaxation. A total of 48 mice were used in this study, including wild-type mice and two different transgenic mouse strains. Different groups of these mice were fed high-fat or low-fat diets or liquid diets with and without the addition of alcohol. Proton spectra were collected at baseline and, subsequently, Alcoholic (1, 2) and nonalcoholic fatty liver (NAFL) (3-7) are highly prevalent in human populations and may develop into steatohepatitis and in some cases into cirrhosis requiring liver transplantation. Animal models of both conditions have been developed. Mouse models are particularly useful because genetic manipulations are highly developed in inbred mice. However, longitudinal studies require the killing of animals because no noninvasive method for quantifying liver fat is available. Here, we describe a noninvasive, nondestructive method for quantifying the liver fat contents of the mouse using a NAFL mouse model. The overwhelming majority of NAFL cases are associated with obesity, dyslipidemia, hypertension, insulin-resistant type 2 diabetes mellitus, and atherosclerotic cardiovascular disease (8)(9)(10)(11)(12). This constellation defines the metabolic syndrome (13,14). One naturally occurring cause of fatty liver is familial hypobetalipoproteinemia (FHBL). FHBL is defined by less than fifth percentile plasma levels of LDL-cholesterol and/or total apolipoprotein B (apoB), segregating in families as an autosomal dominant trait (15-17). The mean liver triglyceride content in apoBimpaired FHBL subjects is 3-to 5-fold greater than that of controls (18,19).In an attempt to understand the cellular/molecular bases of hypobetalipoproteinemia, several recombinant mice mimicking human FHBL have been produced (19)(20)(21)(22)(23)(24)(25). The resulting mice closely resemble their human counterparts with respect to the fatty liver phenotype. Thus, these mice could serve as good models of one genetic form of fatty liver for studies of the progression of fatty liver and on the effects of metabolic, hormonal, and therapeutic perturbations over time.One current limitation of such studies is the absence of an accurate, quantifiable, noninvasive method for repeat assessments of liver fat in animals. In humans, the gold standard for quantifying liver fat is the liver biopsy, which is invasive and, at best, semiquantitative. The analogous procedure in animals is killing of the animal and direct analysis of liver fat by standard chemical methods after extraction. Obviously, direct sampling of livers for fat analysis is not ideal for longitudinal, fol...

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“…In recent years, we (13,14) and other investigators (15)(16)(17) have developed several lines of Apob -modified mice to model the FHBL condition. These mice provided new insights into the FHBL syndrome and the structure-function relationship of apoB-100 (13)(14)(15)(16).…”

mentioning

confidence: 99%

Hepatic secretion of apoB-100 is impaired in hypobetalipoproteinemic mice with an apoB-38.9-specifying allele

Chen

Fitzgerald

et al. 2004

Journal of Lipid Research

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Apolipoprotein B (apoB) truncation-specifying mutations cause familial hypobetalipoproteinemia (FHBL).Lipoprotein kinetics studies have shown that production rates of apoB-100 are reduced by 70-80% in heterozygous FHBL humans, instead of the expected 50%. To develop suitable mouse models to study the underlying mechanism, apoB-38.9-only ( Apob 38.9/38.9 ) mice were crossbred with Apobec-1 knockout ( Apobec-1 ؊ / ؊ ) mice or apoB-100-only ( Apob 100/100 ) mice to produce two lines of apoB-38.9 heterozygous mice that produce only apoB-38.9 and apoB-100, namely Apobec-1 ؊ / ؊ /Apob 38.9/ ؉ and Apob 38.9/100 mice. In vivo rates of apoB-100 secretion were measured using [ 35 S]Met/ Cys to label proteins and Triton WR-1339 to block apoB-100 VLDL lipolysis/uptake. Rates of secretion were reduced by 80%, rather than the expected 50%, in both Apobec-1 ؊ / ؊ / Apob 38.9/ ؉ and Apob 38.9/100 mice compared with those of the respective Apobec-1 ؊ / ؊ /Apob ؉ / ؉ and Apob 100/100 control mice. Continuous labeling and pulse-chase experiments in primary hepatocyte cultures revealed that rates of apoB-100 synthesis by Apobec-1 ؊ / ؊ /Apob 38.9/ ؉ and Apob 38.9/100 hepatocytes were reduced to the expected 50% of those of the respective controls, but the efficiency of secretion of apoB-100 was significantly lower in apoB-38.9 heterozygous hepatocytes. The greater-than-expected decreases in apoB-100 production rates of FHBL heterozygous humans appear to be attributable to a defect in secretion rather than in the synthesis of apoB-100 from the unaffected apoB allele.

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Targeted modification of the apolipoprotein B gene results in hypobetalipoproteinemia and developmental abnormalities in mice.

Cited by 117 publications

References 33 publications

Complexity of vitamin E metabolism

Complexity of vitamin E metabolism

In vivo MRS measurement of liver lipid levels in mice

Hepatic secretion of apoB-100 is impaired in hypobetalipoproteinemic mice with an apoB-38.9-specifying allele

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