Guidance for the diagnosis and treatment of hypolipidemia disorders

Bredefeld, Cindy; Hussain, M. Mahmood; Averna, Maurizio; Black, Dennis D.; Brin, Mitchell F.; Burnett, John R.; Charrière, Sybil; Cuerq, Charlotte; Davidson, Nicholas O.; Deckelbaum, Richard J.; Goldberg, Ira J.; Granot, Esther; Hegele, Robert A.; Ishibashi, Shun; Karmally, Wahida; Lévy, Émile; Moulin, Philippe; Okazaki, Hiroaki; Poinsot, Pierre; Rader, Daniel J.; Takahashi, Manabu; Tarugi, Patrizia; Traber, Maret G.; Filippo, Mathilde Di; Peretti, Noël

doi:10.1016/j.jacl.2022.08.009

Cited by 30 publications

(28 citation statements)

References 126 publications

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“…48 Despite treatment with mega doses of fat-soluble vitamins, ABL patients progressively lose eyesight with age. 63,64 for the first time, we a mouse model in which systemic lipid metabolism is normal but MTP expression in the RPE is deficient. Despite normal systemic lipid levels, RPEΔMttp mice show significant AMD-like ocular abnormalities, such as retinal degeneration, hyperreflective foci, increased lipid deposition, and reduced visual function as determined by ERG.…”

Section: Discussionmentioning

confidence: 99%

Microsomal triglyceride transfer protein is necessary to maintain lipid homeostasis and retinal function

Grubaugh,

Dhingra,

Prakash

et al. 2024

The FASEB Journal

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Lipid processing by the retinal pigment epithelium (RPE) is necessary to maintain retinal health and function. Dysregulation of retinal lipid homeostasis due to normal aging or age‐related disease triggers lipid accumulation within the RPE, on Bruch's membrane (BrM), and in the subretinal space. In its role as a hub for lipid trafficking into and out of the neural retina, the RPE packages a significant amount of lipid into lipid droplets for storage and into apolipoprotein B (APOB)‐containing lipoproteins (Blps) for export. Microsomal triglyceride transfer protein (MTP), encoded by the MTTP gene, is essential for Blp assembly. Herein we test the hypothesis that MTP expression in the RPE is essential to maintain lipid balance and retinal function using the newly generated RPEΔMttp mouse model. Using non‐invasive ocular imaging, electroretinography, and histochemical and biochemical analyses we show that genetic depletion of Mttp from the RPE results in intracellular lipid accumulation, increased photoreceptor‐associated cholesterol deposits, and photoreceptor cell death, and loss of rod but not cone function. RPE‐specific reduction in Mttp had no significant effect on plasma lipids and lipoproteins. While APOB was decreased in the RPE, most ocular retinoids remained unchanged, with the exception of the storage form of retinoid, retinyl ester. Thus suggesting that RPE MTP is critical for Blp synthesis and assembly but is not directly involved in plasma lipoprotein metabolism. These studies demonstrate that RPE‐specific MTP expression is necessary to establish and maintain retinal lipid homeostasis and visual function.

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Section: Discussionmentioning

confidence: 99%

Microsomal triglyceride transfer protein is necessary to maintain lipid homeostasis and retinal function

Grubaugh,

Dhingra,

Prakash

et al. 2024

The FASEB Journal

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“…Abetalipoproteinemia (ABL) patients deficient in MTP activity have low plasma lipids and lipoproteins, as they are unable to synthesize chylomicrons and VLDL in the intestine and liver, respectively. ABL patients progressively lose eyesight with age (50, 51) with retinal dysfunction likely attributable to severe deficiency in the fat-soluble vitamins E and A. Vitamin A is necessary for phototransduction, while Vitamin E is neuroprotective with potent anti-oxidant properties, (6, 52). The highest levels of Vitamin E in the eye are found in RPE (52, 53); in vitro , RPE treated with Vitamin E have less complement activation (54).…”

Section: Discussionmentioning

confidence: 99%

“…The highest levels of Vitamin E in the eye are found in RPE (52, 53); in vitro , RPE treated with Vitamin E have less complement activation (54). Major pathologic consequence of MTP deficiency include angoid streaks, retinitis pigmentosa and loss of vision with age (55–58), despite consumption of mega doses of fat-soluble vitamins (50, 51)…”

Section: Discussionmentioning

confidence: 99%

“…ABL patients show significant ophthalmologic complications (55–58) that are managed with vitamin A and vitamin E supplementation (85–87). Abetalipoproteinemia (ABL) patients deficient in MTP activity have low plasma lipids and lipoproteins and progressive vision loss with age (50, 51). Dietary, fat-soluble vitamin supplementation only delays the onset of vision loss, implicating a role for intestine specific MTP-activity in vision, a hypothesis that can be tested using conditional intestine specific MTP-deficient mice, ENTΔMttp IND .…”

Section: Discussionmentioning

confidence: 99%

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Microsomal triglyceride transfer protein is necessary to maintain lipid homeostasis and retinal function

Grubaugh,

Dhingra,

Prakash

et al. 2023

Preprint

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Lipid processing by the retinal pigment epithelium (RPE) is necessary to maintain retinal health and function. Dysregulation of retinal lipid homeostasis due to normal aging or to age-related disease triggers lipid accumulation within the RPE, on Bruch’s membrane (BrM), and in the subretinal space. In its role as a hub for lipid trafficking into and out of the neural retina, the RPE packages a significant amount of lipid into lipid droplets for storage and into apolipoprotein B (apoB)-containing lipoproteins (Blps) for export. Microsomal triglyceride transfer protein (MTP), encoded by theMTTPgene, is essential for Blp assembly. Herein we test the hypothesis that MTP expression in the RPE is essential to maintain lipid balance and retinal function using the newly generatedRPEΔMttpmouse model. Using non-invasive ocular imaging, electroretinography, and histochemical and biochemical analyses we show that genetic deletion ofMttpfrom the RPE results in intracellular lipid accumulation, increased photoreceptor –associated cholesterol deposits and photoreceptor cell death, and loss of rod but not cone function. RPE-specific ablation of Mttp had no significant effect on plasma lipids and lipoproteins. While, apoB was decreased in the RPE, ocular retinoid concentrations remained unchanged. Thus suggesting that RPE MTP is critical for Blp synthesis and assembly but not directly involved in ocular retinoid and plasma lipoprotein metabolism. These studies demonstrate that RPE-specific MTP expression is necessary to establish and maintain retinal lipid homeostasis and visual function.

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“…Hypobetalipoproteinemia (HBL) is an unique phenotype where their total cholesterol, LDL cholesterol, and apolipoprotein B (APOB) exhibit very low (<5th percentile of sex- and age-matched individuals in the population) [ 1 ]. Heritable primary causes of HBL are currently classified into 2 groups; Class 1: Familial HBL (FHBL) caused by lipoprotein assembly and secretion defects, and Class 2: FHBL caused by enhanced lipoprotein catabolism [ 2 ]. Class 1 includes abetalipoproteinemia (ABL), FHBL caused by LOF variant(s) in APOB (previously called as FHBL1), and chylomicron retention disease (CRD) due to loss-of function (LOF) variant(s) in secretion associated ras related GTPase 1B ( SAR1B ).…”

Section: Introductionmentioning

confidence: 99%

The first Japanese case with familial combined hypolipidemia without any complications caused by loss-of function variants in ANGPTL3: Case report

Tada,

Kojima,

Kawashiri

et al. 2024

Heliyon

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Guidance for the diagnosis and treatment of hypolipidemia disorders

Cited by 30 publications

References 126 publications

Microsomal triglyceride transfer protein is necessary to maintain lipid homeostasis and retinal function

Microsomal triglyceride transfer protein is necessary to maintain lipid homeostasis and retinal function

Microsomal triglyceride transfer protein is necessary to maintain lipid homeostasis and retinal function

The first Japanese case with familial combined hypolipidemia without any complications caused by loss-of function variants in ANGPTL3: Case report

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