Hypobetalipoproteinemia

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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

These are a set of diseases caused my mutations in genes involved in triglyceride(TG), cholesterol transport and metabolism. These diseases primarily cause low plasma LDL C and triglyceride levels.

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.


 
 
 
APOB gene is responsible for the productoion of Apo B48 in intestine which is critical for the formation and secretion of chylomicrons[2] , and Apo B100 in the liver which is released into circulation as VLDL
 
Mutation in the APOB gene affects the translation of mRNA of Apo B. The severity depends whether the patient is homozygous or heterozygous for the mutation.[3].
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
MTP transfers triglycerides from cytsol onto nacent ApoB in endoplasmic reticulum which is required for assembly and secretion of VLDL and chylomicrons.Mutation in MTP causes abetalipoproteinemia[4].
 
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[5]. Mutation in Sar1b causes chylomicron retention disease[6].
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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)[7], 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[8].[9]
 
Loss of function mutations or complete absence of ANGPTL3 gene cause familial combined hypolipidemia [10][11] .
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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[12]
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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)[13].
 
Mutation causing loss of function of the enzyme causes low LDL C levels, and gain of function mutations are associated with familial hypercholesterolemia[14].
 
 

Genetics

Homozygous familial

hypobetalipoproteinemia

Heterozygous familial

hypobetalipoprotienemia

Chylomicron Retention

Disease

Familial Combined

Hypolipidemia

Inheritance Autosomal Codominant Autosomal codominant Autosomal Recessive Autosomal Codominant
Defective Gene APOB gene on chromosome locus 2p23-24 APOB SARA 2 ANGPTL3
Pathophysiology Absence of Apo B

results in absent plasma

VLDL, TG and LDL C.

Truncated Apo B protiens are formed

which affect the lipidation and secretion of the Apo B particles.

These poorly lipidated particles are are rapidly catabolized.

Intracellular transport of chylomicrons is affected ,resulting in the accumalation of lipids intracellularly in the intestine and liver. Loss of function mutation results in the failure of inhibition of Lipoprotien lipase, leading to low LDL, VLDL and HDL levels.

Causes

The following are the list of causes for primary hypobetalipoproteinemia.

  • Abetalipoproteinemia
  • Familial hypobetalipoproteinemia
  • Chylomicron Retention Disease
  • PCSK9 deficiency
  • Familial Combined Hypolipidemia

Natural History, complications and Prognosis

Diagnosis

History and Physical

Homozygous Familial

Hypobetalipoproteinemia

Heterozygous Familial

Hypobetalipoproteinemia

Chylomicron Retention

Disease

Familial Combined

Hypolipidemia

Age of Presentation Infancy Asymptomatic 2months to 1 year Asymptomatic
Clinical Symptoms
  • Steatorrhea, Failure to Thrive.
  • Symptoms progress without treatment to reduced visual acuity, ataxia, dysarthria, loss of vibration and proprioception and areflexia as the posterior columns are affected.
  • Patients are asymptomatic,
  • Common feature is hepatic steatosis[15].
  • Diarrhea, steatorrhea, abdominal distention, and failure to thrive.
  • Normal health

Laboratory Results

Homozygous Familial

Hypobetalipoproteinemia

Heterozygous Familial

Hypobetalipoproteinemia

Chylomicron Retention

Disease

Familial Combined

Hypolipidemia

Lipid analysis
  • ApoB <5th percentile
  • LDL-C between 20- 50 mg/dL
  • LDL C is one third of normal value and not 50% of expected for age and sex.
  • Due to decreased production and increased catabolism of VLDL apo B-100[16]. This causes decreased secretion of triglycerides and low LDL C levels[17].
  • LDL and HDL 50% of normal
  • Normal TG levels.
  • Homozygotes and compound heterozygotes show panhypolipidemia with LDL low TG and reduced HDL C.
  • Heterozygotes  : Normal HDL, with LDL <25th percentile[18].
Other findings
  • Low liposoluble vitamin level.
  • Mild elevation of LFTs
  • Mild elevation of LFTs
  • Failure of chylomicron secretion after a lipid rich meal.
  • Low liposoluble vitamin level.
  • None

Treatment=

Medical Therapy

Surgical Therapy

Prevention

References

  1. 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.
  2. 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.
  3. Di Leo E, Eminoglu T, Magnolo L, Bolkent MG, Tümer L, Okur I; et al. (2015). "The Janus-faced manifestations of homozygous familial hypobetalipoproteinemia due to apolipoprotein B truncations". J Clin Lipidol. 9 (3): 400–5. doi:10.1016/j.jacl.2015.01.005. PMID 26073401.
  4. Berriot-Varoqueaux N, Aggerbeck LP, Samson-Bouma M, Wetterau JR (2000). "The role of the microsomal triglygeride transfer protein in abetalipoproteinemia". Annu Rev Nutr. 20: 663–97. doi:10.1146/annurev.nutr.20.1.663. PMID 10940349.
  5. Shoulders CC, Stephens DJ, Jones B (2004). "The intracellular transport of chylomicrons requires the small GTPase, Sar1b". Curr Opin Lipidol. 15 (2): 191–7. PMID 15017362.
  6. Jones B, Jones EL, Bonney SA, Patel HN, Mensenkamp AR, Eichenbaum-Voline S; et al. (2003). "Mutations in a Sar1 GTPase of COPII vesicles are associated with lipid absorption disorders". Nat Genet. 34 (1): 29–31. doi:10.1038/ng1145. PMID 12692552.
  7. 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.
  8. 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.
  9. 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.
  10. Romeo S, Yin W, Kozlitina J, Pennacchio LA, Boerwinkle E, Hobbs HH; et al. (2009). "Rare loss-of-function mutations in ANGPTL family members contribute to plasma triglyceride levels in humans". J Clin Invest. 119 (1): 70–9. doi:10.1172/JCI37118. PMC 2613476. PMID 19075393.
  11. Robciuc MR, Maranghi M, Lahikainen A, Rader D, Bensadoun A, Öörni K; et al. (2013). "Angptl3 deficiency is associated with increased insulin sensitivity, lipoprotein lipase activity, and decreased serum free fatty acids". Arterioscler Thromb Vasc Biol. 33 (7): 1706–13. doi:10.1161/ATVBAHA.113.301397. PMID 23661675.
  12. 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.
  13. 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.
  14. Marais AD, Kim JB, Wasserman SM, Lambert G (2015). "PCSK9 inhibition in LDL cholesterol reduction: genetics and therapeutic implications of very low plasma lipoprotein levels". Pharmacol Ther. 145: 58–66. doi:10.1016/j.pharmthera.2014.07.004. PMID 25046268.
  15. Tanoli T, Yue P, Yablonskiy D, Schonfeld G (2004). "Fatty liver in familial hypobetalipoproteinemia: roles of the APOB defects, intra-abdominal adipose tissue, and insulin sensitivity". J Lipid Res. 45 (5): 941–7. doi:10.1194/jlr.M300508-JLR200. PMID 14967820.
  16. Welty FK, Lichtenstein AH, Barrett PH, Dolnikowski GG, Ordovas JM, Schaefer EJ (1997). "Decreased production and increased catabolism of apolipoprotein B-100 in apolipoprotein B-67/B-100 heterozygotes". Arterioscler Thromb Vasc Biol. 17 (5): 881–8. PMID 9157951.
  17. Elias N, Patterson BW, Schonfeld G (1999). "Decreased production rates of VLDL triglycerides and ApoB-100 in subjects heterozygous for familial hypobetalipoproteinemia". Arterioscler Thromb Vasc Biol. 19 (11): 2714–21. PMID 10559016.
  18. Minicocci I, Montali A, Robciuc MR, Quagliarini F, Censi V, Labbadia G; et al. (2012). "Mutations in the ANGPTL3 gene and familial combined hypolipidemia: a clinical and biochemical characterization". J Clin Endocrinol Metab. 97 (7): E1266–75. doi:10.1210/jc.2012-1298. PMID 22659251.

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