Hypobetalipoproteinemia: Difference between revisions
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{{Family tree | | | | A01 | | | |A01= Apo B48 is produced in intestine and is critical in the formation and secretion of chylomicrons<ref name="pmid25974693">{{cite journal| author=Dash S, Xiao C, Morgantini C, Lewis GF| title=New Insights into the Regulation of Chylomicron Production. | journal=Annu Rev Nutr | year= 2015 | volume= 35 | issue= | pages= 265-94 | pmid=25974693 | doi=10.1146/annurev-nutr-071714-034338 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25974693 }} </ref> , Apo B100 is synthesized in liver and released into circulation as VLDL}} | {{Family tree | | | | A01 | | | |A01= Apo B48 is produced in intestine and is critical in the formation and secretion of chylomicrons<ref name="pmid25974693">{{cite journal| author=Dash S, Xiao C, Morgantini C, Lewis GF| title=New Insights into the Regulation of Chylomicron Production. | journal=Annu Rev Nutr | year= 2015 | volume= 35 | issue= | pages= 265-94 | pmid=25974693 | doi=10.1146/annurev-nutr-071714-034338 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25974693 }} </ref> , Apo B100 is synthesized in liver and released into circulation as VLDL}} | ||
{{Family tree | | | | |!| | | | | }} | {{Family tree | | | | |!| | | | | }} | ||
{{Family tree | | | | B01 | | | |B01= MTP transfers triglycerides from cytsol onto nacent ApoB in endoplasmic reticulum which is required for assembly and secretion of VLDL and chylomicrons}} | {{Family tree | | | | B01 |-| B02| |B01= MTP transfers triglycerides from cytsol onto nacent ApoB in endoplasmic reticulum which is required for assembly and secretion of VLDL and chylomicrons|B02= In Apo B48 associated chylomicrons, transport of protiens from endoplasmic reticulum to golgi complex is dependent on coat protien complex 2(COP II), secretion-associated, Ras-related GTPase 1B (Sar1b) encoded by the gene SARA2 is a major part of the protein essential for this intra cellular transport}} | ||
{{Family tree | | | | |!| | | | | }} | {{Family tree | | | | |!| | | | | }} | ||
{{Family tree | | | | C01 | | | |C01= In the periphery by the action of lipoprotein lipase in the endothelium of the capillaries and glycosylphosphatidylinositol-anchored high-density lipoprotein- binding protein 1 (GPIHBP1)<ref name="pmid21844202">{{cite journal| author=Young SG, Davies BS, Voss CV, Gin P, Weinstein MM, Tontonoz P et al.| title=GPIHBP1, an endothelial cell transporter for lipoprotein lipase. | journal=J Lipid Res | year= 2011 | volume= 52 | issue= 11 | pages= 1869-84 | pmid=21844202 | doi=10.1194/jlr.R018689 | pmc=3196223 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21844202 }} </ref>, a transporter for lipoprotien lipase triglycerides are hydrolysed to form free fatty acids and glycerol }} | {{Family tree | | | | C01 | | | |C01= In the periphery by the action of lipoprotein lipase in the endothelium of the capillaries and glycosylphosphatidylinositol-anchored high-density lipoprotein- binding protein 1 (GPIHBP1)<ref name="pmid21844202">{{cite journal| author=Young SG, Davies BS, Voss CV, Gin P, Weinstein MM, Tontonoz P et al.| title=GPIHBP1, an endothelial cell transporter for lipoprotein lipase. | journal=J Lipid Res | year= 2011 | volume= 52 | issue= 11 | pages= 1869-84 | pmid=21844202 | doi=10.1194/jlr.R018689 | pmc=3196223 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21844202 }} </ref>, a transporter for lipoprotien lipase triglycerides are hydrolysed to form free fatty acids and glycerol }} | ||
Revision as of 17:56, 15 November 2016
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Aravind Kuchkuntla, M.B.B.S[2]
Synonyms and keywords: Familial hypobetalipoproteinemia, FHBL, normotriglyceridemic hypobetalipoproteinemia
Overview
It is a rare disease caused by mutation in the APOB gene or less commonly in the PCSK9 gene, characteristic findings include low plasma level of total cholesterol, low LDL C, and Apo B below the 5th percentile when compared to the normal population.
Historical Perspective
- In 1960, Salt reported absence of betalipoprotein in the plasma of a patient associated with very low cholesterol levels in the parents. Low cholesterol levels in the parents differentiates it from abetalipoproteinemia[1].
Pathophysiology
Pathogenesis
- Cholesterol and triglycerides are insolublei in the plasma, so they require a transport protien in the form of apolipoprotein B. These lipoproteins transport cholesterol and trigylcerides in spherical particles in which the cholesterol esters and triglyceride form the central core.
- Apolipoprotein B is the major carrier for triglycerides and cholesterol from the intestine and liver to the periphery.
- Apo B exits in two forms, Apo B48 and Apo B100.
| Apo B48 is produced in intestine and is critical in the formation and secretion of chylomicrons[2] , Apo B100 is synthesized in liver and released into circulation as VLDL | |||||||||||||||||||||
| MTP transfers triglycerides from cytsol onto nacent ApoB in endoplasmic reticulum which is required for assembly and secretion of VLDL and chylomicrons | In Apo B48 associated chylomicrons, transport of protiens from endoplasmic reticulum to golgi complex is dependent on coat protien complex 2(COP II), secretion-associated, Ras-related GTPase 1B (Sar1b) encoded by the gene SARA2 is a major part of the protein essential for this intra cellular transport | ||||||||||||||||||||
| In the periphery by the action of lipoprotein lipase in the endothelium of the capillaries and glycosylphosphatidylinositol-anchored high-density lipoprotein- binding protein 1 (GPIHBP1)[3], a transporter for lipoprotien lipase triglycerides are hydrolysed to form free fatty acids and glycerol | |||||||||||||||||||||
| This results in the formation of VLDL remnant( Intermediate density lipoprotein) and chylomicron remnants The lipases are inhibited by Angiopoietin-like protein 3 (ANGPTL3) thereby decreasing the triglyceride and LDL C[4].[5] | |||||||||||||||||||||
| IDL on further removal of triglycerides forms a cholesterol ester rich LDL C, the chylomicron and VLDL remnants removal is Apo E dependent via the LDL receptors and LDL receptor related protiens[6] | |||||||||||||||||||||
| LDL C is removed from the circulation by binding to LDL receptors in the liver. The receptor degradation is enhanced by Proprotein convertase subtilisin kexin 9 (PCSK9)[7], any mutation in the loss of function in the enzyme causes low LDL C levels | |||||||||||||||||||||
Genetics
- Mutation in the APOB gene on chromosome 2p24 which codes for apolipoprotein B.
- Mutation in the PCSK9 can also cause the disease but it is less common compared to the mutation in Apo B.
- Familial hypobetalipoproteinemia-2 is caused by mutation in the ANGPTL3 gene (604774) on chromosome 1p31.
Natural History, complications and Prognosis
Diagnosis
History and Physical
Laboratory Results
Treatment=
Medical Therapy
Surgical Therapy
Prevention
Hypobetalipoproteinemia is a rare autosomal dominant genetic disorder causing abnormally low levels of LDL cholesterol and apolipoprotein B.[8] It is thought to be caused by a mutation in apolipoprotein B.[9] The patient can have low LDL level and simultaneously have high levels of HDL cholesterol. Typically in hypobtalipoproteinemia, plasma cholesterol levels will be around 80-120 mg/dL, LDL cholesterol will be around 50-80 mg/dL, and longevity can be expected with good nutrition. Affected individuals can be either homozygous or heterozygous, the latter being most commonly asymptomatic.[9]
Normotriglyceridemic hypobetalipoproteinemia, formally called normotriglyceridemic abetalipoproteinemia, is a condition characterized by absence of LDLs and apoB100 and normal triglyceride-rich lipoproteins.[10][11]
References
- ↑ SALT HB, WOLFF OH, LLOYD JK, FOSBROOKE AS, CAMERON AH, HUBBLE DV (1960). "On having no beta-lipoprotein. A syndrome comprising a-beta-lipoproteinaemia, acanthocytosis, and steatorrhoea". Lancet. 2 (7146): 325–9. PMID 13745738.
- ↑ Dash S, Xiao C, Morgantini C, Lewis GF (2015). "New Insights into the Regulation of Chylomicron Production". Annu Rev Nutr. 35: 265–94. doi:10.1146/annurev-nutr-071714-034338. PMID 25974693.
- ↑ Young SG, Davies BS, Voss CV, Gin P, Weinstein MM, Tontonoz P; et al. (2011). "GPIHBP1, an endothelial cell transporter for lipoprotein lipase". J Lipid Res. 52 (11): 1869–84. doi:10.1194/jlr.R018689. PMC 3196223. PMID 21844202.
- ↑ Shan L, Yu XC, Liu Z, Hu Y, Sturgis LT, Miranda ML; et al. (2009). "The angiopoietin-like proteins ANGPTL3 and ANGPTL4 inhibit lipoprotein lipase activity through distinct mechanisms". J Biol Chem. 284 (3): 1419–24. doi:10.1074/jbc.M808477200. PMC 3769808. PMID 19028676.
- ↑ Yoshida K, Shimizugawa T, Ono M, Furukawa H (2002). "Angiopoietin-like protein 4 is a potent hyperlipidemia-inducing factor in mice and inhibitor of lipoprotein lipase". J Lipid Res. 43 (11): 1770–2. PMID 12401877.
- ↑ Lillis AP, Van Duyn LB, Murphy-Ullrich JE, Strickland DK (2008). "LDL receptor-related protein 1: unique tissue-specific functions revealed by selective gene knockout studies". Physiol Rev. 88 (3): 887–918. doi:10.1152/physrev.00033.2007. PMC 2744109. PMID 18626063.
- ↑ Garvie CW, Fraley CV, Elowe NH, Culyba EK, Lemke CT, Hubbard BK; et al. (2016). "Point mutations at the catalytic site of PCSK9 inhibit folding, autoprocessing, and interaction with the LDL receptor". Protein Sci. 25 (11): 2018–2027. doi:10.1002/pro.3019. PMC 5079255. PMID 27534510.
- ↑ Musunuru K, Pirruccello JP, Do R, Peloso GM, Guiducci C, Sougnez C; et al. (2010). "Exome sequencing, ANGPTL3 mutations, and familial combined hypolipidemia". N Engl J Med. 363 (23): 2220–7. doi:10.1056/NEJMoa1002926. PMC 3008575. PMID 20942659.
- ↑ 9.0 9.1 Schonfeld G, Lin X, Yue P (2005). "Familial hypobetalipoproteinemia: genetics and metabolism". Cell Mol Life Sci. 62 (12): 1372–8. doi:10.1007/s00018-005-4473-0. PMID 15818469.
- ↑ Harano Y, Kojima H, Nakano T, Harada M, Kashiwagi A, Nakajima Y; et al. (1989). "Homozygous hypobetalipoproteinemia with spared chylomicron formation". Metabolism. 38 (1): 1–7. PMID 2909827.
- ↑ Herbert PN, Hyams JS, Bernier DN, Berman MM, Saritelli AL, Lynch KM; et al. (1985). "Apolipoprotein B-100 deficiency. Intestinal steatosis despite apolipoprotein B-48 synthesis". J Clin Invest. 76 (2): 403–12. doi:10.1172/JCI111986. PMC 423826. PMID 4031057.
- ↑ Biemer JJ, McCammon RE (1975). "The genetic relationship of abetalipoproteinemia and hypobetalipoproteinemia: a report of the occurence of both diseases within the same family". J Lab Clin Med. 85 (4): 556–65. PMID 164511.