New Classification and Management of Abetalipoproteinemia and Related Disorders

Bredefeld, Cindy; Peretti, Noël; Hussain, M. Mahmood; Filippo, Mathilde Di; Granot, E; Cuerq, Charlotte; Poinsot, Pierre; Moulin, Philippe; Charrière, Sybil; Brin, Mitchell F.; Deckelbaum, Richard J.; Black, Dennis D.

doi:10.1053/j.gastro.2020.11.040

Cited by 24 publications

(16 citation statements)

References 22 publications

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“…Hallmark symptoms are fat malabsorption or steatorrhea, spinocerebellar degeneration, acanthocyte red blood cells, and retinitis pigmentosa. These patients may also show symptoms of deficiencies of lipid-soluble vitamins (A, E, D, and K) [ 147 , 148 ].…”

Section: Causes Of Nutrient Malabsorptionmentioning

confidence: 99%

Small and Large Intestine (I): Malabsorption of Nutrients

2021

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Numerous disorders can alter the physiological mechanisms that guarantee proper digestion and absorption of nutrients (macro- and micronutrients), leading to a wide variety of symptoms and nutritional consequences. Malabsorption can be caused by many diseases of the small intestine, as well as by diseases of the pancreas, liver, biliary tract, and stomach. This article provides an overview of pathophysiologic mechanisms that lead to symptoms or complications of maldigestion (defined as the defective intraluminal hydrolysis of nutrients) or malabsorption (defined as defective mucosal absorption), as well as its clinical consequences, including both gastrointestinal symptoms and extraintestinal manifestations and/or laboratory abnormalities. The normal uptake of nutrients, vitamins, and minerals by the gastrointestinal tract (GI) requires several steps, each of which can be compromised in disease. This article will first describe the mechanisms that lead to poor assimilation of nutrients, and secondly discuss the symptoms and nutritional consequences of each specific disorder. The clinician must be aware that many malabsorptive disorders are manifested by subtle disorders, even without gastrointestinal symptoms (for example, anemia, osteoporosis, or infertility in celiac disease), so the index of suspicion must be high to recognize the underlying diseases in time.

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Section: Causes Of Nutrient Malabsorptionmentioning

confidence: 99%

Small and Large Intestine (I): Malabsorption of Nutrients

2021

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“…These monogenic disorders were recently classified into 2 classes based on molecular mechanisms: FHBL attributable to lipoprotein secretion defects (FHBL-SD1, -SD2, and -SD3 for MTTP , APOB , and SAR1B -related FHBL) or to enhanced catabolism of apolipoprotein B (apoB)–containing lipoprotein (FHBL-EC1 and -EC2 for ANGPTL3 - and PCSK9 -related FHBL). 6 Furthermore, pathogenic variants in the ANGPTL3 gene have been identified in cases of familial combined hypolipidemia, a condition characterized by very low concentrations of circulating very-low-density lipoprotein (VLDL), LDL, and HDL. 7 Despite the suspected polygenic origins of unexplained cases of extremely elevated or reduced LDL-C concentrations, polygenic risk scores have so far yielded lower effect sizes compared with the effect of monogenic variants.…”

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confidence: 99%

Identification of a Gain-of-Function LIPC Variant as a Novel Cause of Familial Combined Hypocholesterolemia

et al. 2022

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Background: Atherosclerotic cardiovascular disease is the main cause of mortality worldwide and is strongly influenced by circulating low-density lipoprotein (LDL) cholesterol levels. Only a few genes causally related to plasma LDL cholesterol levels have been identified so far, and only 1 gene, ANGPTL3 , has been causally related to combined hypocholesterolemia. Here, our aim was to elucidate the genetic origin of an unexplained combined hypocholesterolemia inherited in 4 generations of a French family. Methods: Using next-generation sequencing, we identified a novel dominant rare variant in the LIPC gene, encoding for hepatic lipase, which cosegregates with the phenotype. We characterized the impact of this LIPC -E97G variant on circulating lipid and lipoprotein levels in family members using nuclear magnetic resonance–based lipoprotein profiling and lipidomics. To uncover the mechanisms underlying the combined hypocholesterolemia, we used protein homology modeling, measured triglyceride lipase and phospholipase activities in cell culture, and studied the phenotype of APOE*3.Leiden.CETP mice after LIPC -E97G overexpression. Results: Family members carrying the LIPC -E97G variant had very low circulating levels of LDL cholesterol and high-density lipoprotein cholesterol, LDL particle numbers, and phospholipids. The lysophospholipids/phospholipids ratio was increased in plasma of LIPC -E97G carriers, suggestive of an increased lipolytic activity on phospholipids. In vitro and in vivo studies confirmed that the LIPC -E97G variant specifically increases the phospholipase activity of hepatic lipase through modification of an evolutionarily conserved motif that determines substrate access to the hepatic lipase catalytic site. Mice overexpressing human LIPC -E97G recapitulated the combined hypocholesterolemic phenotype of the family and demonstrated that the increased phospholipase activity promotes catabolism of triglyceride-rich lipoproteins by different extrahepatic tissues but not the liver. Conclusions: We identified and characterized a novel rare variant in the LIPC gene in a family who presents with dominant familial combined hypocholesterolemia. This gain-of-function variant makes LIPC the second identified gene, after ANGPTL3 , causally involved in familial combined hypocholesterolemia. Our mechanistic data highlight the critical role of hepatic lipase phospholipase activity in LDL cholesterol homeostasis and suggest a new LDL clearance mechanism.

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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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New Classification and Management of Abetalipoproteinemia and Related Disorders

Cited by 24 publications

References 22 publications

Small and Large Intestine (I): Malabsorption of Nutrients

Small and Large Intestine (I): Malabsorption of Nutrients

Identification of a Gain-of-Function LIPC Variant as a Novel Cause of Familial Combined Hypocholesterolemia

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

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