ABC1: Connecting Yellow Tonsils, Neuropathy, and Very Low HDL

ABC1: connecting yellow tonsils, neuropathy, and very low HDL

Helen H. Hobbs, Daniel J. Rader

J Clin Invest. 1999;104(8):1015-1017. https://doi.org/10.1172/JCI8509.

Commentary

In 1960, the most common surgical procedure performed on children was tonsillectomy. During one such routine operation, an astute physician recognized that the tonsils of his 5-year-old patient from Tangier Island were anything but ordinary (1). The tonsils were strikingly large, lobulated, and lemon-colored. The tonsils of the patient’s sister were similarly abnormal in appearance and had a 50- to 100-fold elevated content of cholesteryl ester. The siblings also shared another remarkable trait: both had extremely low plasma levels of HDL cholesterol (HDL-C). These children were the index cases of Tangier disease, a genetic disorder characterized by an abnormal plasma lipoprotein profile — virtual absence of HDL-C, reduced levels of LDL cholesterol (LDL-C) with mildly or moderately elevated triglycerides, and a variety of seemingly disparate clinical findings, such as hepatosplenomegaly and peripheral neuropathy (2). The multifaceted manifestations of this disorder have inspired (and frustrated) more clinicians and scientists than there are patients with the disease. A breakthrough in our understanding of this enigmatic disease came recently when 3 groups identified the underlying molecular defect to be mutations in the ATP binding cassette transporter 1 (ABC1) gene (3–5). The report by Lawn et al. in this issue of the JCI extends these findings and provides a further functional characterization of the ABC1 transporter (6). These discoveries, which explain some of the […]

Find the latest version: https://jci.me/8509/pdf ABC1: connecting yellow tonsils, Commentary neuropathy, and very low HDL See related article in this issue, pages R25–R31.

Helen H. Hobbs1 and Daniel J. Rader2 1Departments of Internal Medicine and Molecular Genetics, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75229, USA 2Departments of Internal Medicine and Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA Address correspondence to: Helen H. Hobbs, Department of Molecular Genetics, University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Boulevard, Dallas, Texas 75229, USA. Phone: (214) 648-6724; Fax: (214) 648-7539; E-mail: [email protected].

In 1960, the most common surgical pro- arily conserved transmembrane pro- HDL (10). The full complement of cedure performed on children was ton- teins that transport a wide variety of substrates transported by ABC1 has sillectomy. During one such routine substrates, including ions, drugs, pep- not been identified, and it is possible operation, an astute physician recog- tides, and lipids, across cell mem- that some of the variability in the clin- nized that the tonsils of his 5-year-old branes (7). Mutations in other family ical manifestations of this disease is patient from Tangier Island were any- members cause a variety of genetic dis- due to mutation-specific differences thing but ordinary (1). The tonsils were orders, such as cystic fibrosis, intra- in substrate specificity. strikingly large, lobulated, and lemon- hepatic cholestasis, macular degener- Yellow/orange tonsils. What does Tang- colored. The tonsils of the patient’s sister ation, peroxisomal dysfunction, and ier disease teach us about the function were similarly abnormal in appearance immunodeficiency syndromes (7). of ABC1 and the importance of facili- and had a 50- to 100-fold elevated con- The first clue that ABC1 participated tated cholesterol efflux in human tent of cholesteryl ester. The siblings also in lipid metabolism came with the physiology? Despite near-ubiquitous shared another remarkable trait: both observation by Schmitz and col- expression of ABC1 (8), the cholesterol had extremely low plasma levels of HDL leagues that ABC1 expression rose accumulation in Tangier disease cholesterol (HDL-C). These children when the cholesterol content of appears to be restricted primarily to were the index cases of Tangier disease, a macrophages was increased (8). In an macrophages and to other cells of the genetic disorder characterized by an independent study using expression reticuloendothelial system. This sug- abnormal plasma lipoprotein profile — microarrays, Lawn et al. identified the gests that other cell types are better virtual absence of HDL-C, reduced levels ABC1 mRNA as an upregulated tran- able to control lipid entry and may not of LDL cholesterol (LDL-C) with mildly script in cholesterol-loaded be as dependent on facilitated efflux. or moderately elevated triglycerides, and macrophages (6). Macrophages rou- The hallmark yellow and/or orange a variety of seemingly disparate clinical tinely ingest large amounts of choles- discoloration of the tonsils, adenoids, findings, such as hepatosplenomegaly terol in the form of cellular membrane and colonic reticuloendothelial cells in and peripheral neuropathy (2). The mul- debris and aggregated lipoproteins, this disease may be due to the accu- tifaceted manifestations of this disorder and lack the ability to downregulate mulation in these cells of lipophilic have inspired (and frustrated) more cli- cholesterol uptake in response to cho- compounds such as vitamin E and nicians and scientists than there are lesterol loading (9). Consequently, retinyl esters (yellow) and carotenoids patients with the disease. macrophages are heavily dependent (orange). This feature of the disease A breakthrough in our understanding on cholesterol efflux (predominantly now raises the possibility that ABC1 is of this enigmatic disease came recently through transfer to HDL) to prevent also responsible for transporting when 3 groups identified the underlying accumulation of lipids. Thus, it might excess fat-soluble vitamins out of molecular defect to be mutations in the be anticipated that proteins that par- macrophages. ATP binding cassette transporter 1 ticipate in cholesterol efflux, such as Neuropathy. In patients with Tangier (ABC1) gene (3–5). The report by Lawn ABC1, would be increased in choles- disease, lipids also accumulate within et al. in this issue of the JCI extends terol-laden macrophages. The current Schwann cells, which synthesize and these findings and provides a further finding of Lawn et al. that ABC1 is maintain the myelin sheaths of functional characterization of the ABC1 located on the cell surface suggests peripheral nerves. The most debilitat- transporter (6). These discoveries, which that this transporter may actually ing feature of the disease is neuropa- explain some of the variable clinical physically participate in the hand-off thy, which affects approximately 50% manifestations of Tangier disease, will of cholesterol from cells to plasma of Tangier patients (2). Two major provide new insights not only into the HDL (6). This finding dovetails nicely types of neurological syndromes are physiology and cell biology of lipid with the previous observation that observed: (a) a syringomyelia-like dis- metabolism, but also into neurobiology Tangier fibroblasts have a greatly order, with progressive loss of sensory and possibly even atherosclerosis. reduced capacity to donate cellular and motor function in the upper ABC1 and cholesterol efflux. ABC1 cholesterol (and phospholipids) to body; and (b) a peripheral neuropathy, belongs to a large family of evolution- apo A-I, the major apolipoprotein of with remitting loss of peripheral sen-

The Journal of Clinical Investigation | October 1999 | Volume 104 | Number 8 1015 sory and/or motor function. It is not have markedly elevated plasma levels abnormal particles (18) and may be yet known whether different molecu- of LDL-C (mean ∼300 mg/dL), have a associated with symptomatic improve- lar defects in ABC1 are associated with 3- to 4-fold higher risk of premature ment in the peripheral neuropathy each of these mutually exclusive neu- CAD (≤60 years old) than do those (H.H. Hobbs, personal observation). rological subtypes. The major patho- with Tangier disease, who have virtual- The generalized abnormalities among logical findings on peripheral nerve ly no plasma HDL-C (13, 16). Tangier all lipoprotein classes in Tangier dis- biopsy are neuronal loss and lipid patients may have less risk than other- ease illuminate the close link between accumulation in Schwann cells (2). wise expected, because their plasma the metabolism of HDL and the apo The cause of nerve death in this disor- LDL-C levels are also very low (∼40% of B–containing lipoproteins. der is not known, but nerve loss normal, or mean plasma LDL-C ∼50 Therapeutic implications. ABC1 and the appears to precede the development of mg/dL) (2, 14). In epidemiological entire reverse cholesterol transport the lipid-laden Schwann cells (11). studies, individuals with plasma levels pathway present enticing targets for ABC1 may limit the accumulation of of LDL less than ∼80 mg/dL rarely the development of new therapies for toxic substances within neurons by develop CAD (17). Thus, the fact that atherosclerosis. Although reduction of mediating their removal, hence pro- Tangier patients develop CAD to a LDL-C is the crucial factor in reducing viding protection from neuronal cell greater extent than do normal individ- cardiovascular risk, LDL lowering fails injury and death; precedent for such a uals, despite having very low LDL-C to halt the progression of atheroscle- role comes from study of another ABC levels, suggests that impaired cellular rosis in some subjects (20). Pharmaco- family member, the multiple drug efflux or the associated abnormalities logic manipulation of the reverse cho- resistance 1 protein (12). Engorged in the other classes of lipoproteins (see lesterol transport pathway — by Schwann cells presumably arise below) promotes atherosclerosis. increasing cellular ABC1 expression to because of the inability of these cells Low HDL-C and LDL-C, and elevated augment cellular efflux of cholesterol to export lipids acquired from scav- triglycerides. The major cause of the to HDL, by preventing the catabolism enged dead neurons. markedly reduced plasma levels of of HDL without interfering with its Coronary artery disease. The other clin- HDL and apo A-I in Tangier disease cholesterol transport function, or by ically significant sequela of defects in appears to be an inability of HDL to increasing the rate of hepatic HDL ABC1 is an increased incidence of coro- acquire sufficient cholesterol from cholesterol uptake — may provide new nary artery disease (CAD) (13, 14). Even cells to maintain its metabolic integri- strategies against a disease that is the obligate heterozygotes, who have ty, resulting in markedly accelerated major cause of human morbidity and reduced plasma levels of HDL-C, have HDL catabolism (2). However, the rea- mortality. an increased risk of CAD (13). The pre- son that defective cholesterol efflux The elucidation of the molecular eti- vailing view is that subjects with Tangi- results in such low plasma levels of ology of Tangier disease illustrates er disease are at higher risk for develop- LDL-C remains mysterious. A reduc- once again how the weaving together ing atherosclerosis, because of a tion in HDL-mediated return of cho- of the independent strands of basic reduction in the rate of reverse choles- lesterol from the periphery to the liver research in cell biology and the clinical terol transport, the process by which may alter hepatic lipid metabolism, observations of a rare inherited phe- cholesterol is transported from the resulting in the decreased production notype can provide a new fabric for the periphery to the liver. ABC1 partici- or lowered cholesterol content of LDL understanding of a major physiologi- pates in the first and most poorly precursor lipoproteins. Alternatively, cal pathway. understood step in the reverse choles- this altered metabolic pattern may terol transport pathway — the transfer promote hepatic LDL receptor activity, 1. Fredrickson, D.S., Altrocchi, P.H., Avioli, L.V., of cholesterol from cells to HDL. A which would increase the rate of Goodman, D.S., and Goodman, H.C. 1961. Tangier disease: combined clinical staff confer- defect in the function of ABC1 would removal of LDL from the plasma. It is ence at the National Institutes of Health. be expected to result in the accumula- also possible that the failure to trans- 55:1016–1031. tion of cholesteryl esters in fer cholesterol from HDL to LDL and 2. Assman, G., von Eckardstein, A., and Brewer, H.B. 1995. Familial high density lipoprotein deficien- macrophages in the arterial wall, which VLDL leads to cholesterol-poor LDL, cy: Tangier disease. In The metabolic and molecular may promote atherosclerosis. A major which may be metabolized more rap- bases of inherited disease. C.R. Scriver, A.L. Beaudet, unanswered question is the extent to idly than cholesterol-rich LDL. and W.S. Sly, editors. McGraw-Hill. New York, NY. 2053–2072. which ABC1-mediated cholesterol The metabolism of intestinally 3. Bodzioch, M., et al. 1999. The gene encoding efflux contributes to total-body reverse derived and hepatically derived triglyc- ATP-binding cassette transporter 1 is mutated in cholesterol transport, a question that eride-rich lipoproteins (chylomicrons Tangier disease. Nat. Genet. 22:347–351. 4. Rust, S., et al. 1999. Tangier disease is caused by could be addressed using an Abc1- and VLDL, respectively) is also mutations in the gene encoding ATP-binding cas- knockout mouse. The Wisconsin Hypo- deranged in Tangier patients (18). sette transporter 1. Nat. Genet. 22:352–355. Alpha Mutant (WHAM) chicken may These particles are markedly distorted 5. Brooks-Wilson, A., et al. 1999. Mutations in ABC1 in Tangier disease and familial high-density provide a natural animal model for this in appearance and exceedingly variable lipoprotein deficiency. Nat. Genet. 22:336–345. disorder (15). in size, and thus may be scavenged by 6. Lawn, R.M., et al. 1999. The Tangier disease gene Although the risk for early athero- the reticuloendothelial system. In sup- product ABC1 controls the cellular apolipoprotein-mediated lipid removal pathway. J. Clin. sclerosis is enhanced in Tangier dis- port of this notion, one Tangier Invest. 104:R25-R31. ease, this increase is not as dramatic as patient experienced a doubling in his 7. Higgins, C.F. 1992. ABC transporters: from might be expected (13, 14). As a com- non-HDL plasma cholesterol after microorganisms to man. Annu. Rev. Cell Biol. 8:67–113. parison, adults with heterozygous splenectomy (19). Initiation of a low- 8. Langmann, T., et al. 1999. 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