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Review
. 2014 Jun;25(3):161-8.
doi: 10.1097/MOL.0000000000000072.

Hypobetalipoproteinemia and abetalipoproteinemia

Francine K Welty  1
Affiliations
Review

Hypobetalipoproteinemia and abetalipoproteinemia

Francine K Welty. Curr Opin Lipidol. 2014 Jun.

Abstract

Purpose of review: Several mutations in the apoB, proprotein convertase subtilisin/kexin type 9 (PCSK9), and MTP genes result in low or absent levels of apoB and LDL-cholesterol in plasma, which cause familial hypobetalipoproteinemia and abetalipoproteinemia. Mutations in the ANGPTL3 gene cause familial combined hypolipidemia. Clinical manifestations range from none to severe, debilitating, and life-threatening disorders. This review summarizes recent genetic, metabolic, and clinical findings and presents an update on management strategies.

Recent findings: Cases of cirrhosis and hepatocellular carcinoma have now been identified in heterozygous familial hypobetalipoproteinemia probably because of decreased triglyceride transport capacity from the liver. ANGPTL3 mutations cause low levels of LDL-cholesterol and low HDL-cholesterol in compound heterozygotes and homozygous individuals, decrease reverse cholesterol transport, and lower glucose levels. The effect on atherosclerosis is unknown; however, severe fatty liver has been identified. Loss-of-function mutations in PCSK9 cause familial hypobetalipoproteinemia, which appears to lower risk for coronary artery disease and has no adverse sequelae. Phase III clinical trials are now underway examining the effect of PCSK9 inhibitors on cardiovascular events in combination with statin drugs.

Summary: Mutations causing low LDL-cholesterol and apoB have provided insight into lipid metabolism, disease associations, and the basis for drug development to lower LDL-cholesterol in disorders causing high levels of cholesterol. Early diagnosis and treatment are necessary to prevent adverse sequelae from familial hypobetalipoproteinemia and abetalipoproteinemia.

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Conflict of interest statement

Conflict of Interest: None

Figures

Figure 1
Figure 1
Overview of lipid metabolism showing location and mechanisms of the various mutations in the apolipoprotein (apo) B, microsomal triglyceride transfer protein (MTP), proprotein convertase subtilisin kexin 9 (PCSK9) and angiopoietin-like protein 3 (ANGPTL3) genes which cause familial hypobetalipoproteinemia (FHBL), combined hypolipidemia (cHLP) and abetalipoproteinemia (ABL). Briefly, MTP catalyzes transfer of triglyceride (TG) onto the nascent apoB particle in intestinal and hepatic cells, forming chylomicrons (CM) and very low-density lipoprotein (VLDL), respectively. Mutations in MTP decrease this transfer and therefore, decrease the formation of CM and VLDL, a process leading to near absence of LDL-C and apoB in the plasma and causing ABL. Mutations in the apoB gene decrease formation and secretion of VLDL apoB-100 from the liver which leads to decreased levels of LDL-C and causes FHBL. Loss of function mutations in PCSK9 decrease the degradation of the LDL-receptor (LDL-R) and thus make more LDL-R available on the surface of the liver, thereby lowering LDL-C levels and causing FHBL. Loss of function mutations in ANGPTL3 cause increased activity of lipoprotein lipase (LPL) and endothelial lipase (EL) and thus lower the levels of LDL-C, TG and HDL-C, leading to combined hypolipidemia. X denotes a mutation or loss of a pathway; ec: endothelial cell; CMR: chylomicron remnant; ox: oxidized; CE: cholesterol ester; CETP: cholesterol ester transfer protein.
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