The genetic basis of primary disorders of intestinal fat transport

Émile Levy, PhD

From the Division of Gastroenterology­Nutrition, Hôpital Sainte-Justine, Montreal, Que.

Clin Invest Med 1996; 19 (5): 317-24.

[résumé]

Paper reprints may be obtained from: Dr. Emile Levy, Division of Gastroenterology­Nutrition, Hôpital Sainte-Justine, 3175 Côte Sainte-Catherine, Montreal QC H3T 1C5; fax 514 345-4999

Contents

Abstract

For decades, research interest has focused on hypertriglyceridemia and hypercholesterolemia, because of their association with atherosclerosis. Recently, however, increasing attention has been paid to rare hypolipidemic states that can cause adverse consequences in young patients. Studies of genetic disorders of fat transport have afforded new insights into the mechanisms involved in intestinal lipid handling and lipoprotein metabolism. This article reviews briefly the current state of knowledge about inherited lipoprotein deficiencies, including abetalipoproteinemia, hypobetalipoproteinemia and chylomicron retention disease. These disorders share many common characteristics: they all cause fat malabsorption, low levels of circulating lipids and fat-soluble vitamins, failure to thrive in early childhood, ataxic neuropathy and visual impairment. However, their etiology is genetically different. Abetalipoproteinemia is caused by the absence of microsomal transfer protein, whereas hypobetalipoproteinemia is due to defects in the apolipoprotein B gene. The etiopathogenesis of chylomicron retention disease is as yet unexplained. Research on these rare, inherited fat disorders of absorption will continue to provide significant advances in our understanding of human physiology and may yield novel therapeutic approaches to atherosclerosis.

Résumé

Depuis plusieurs décennies, les efforts de recherche se sont concentrés sur l'hypertriglycéridémie et l'hypercholestérolémie à cause de leur association avec l'athérosclérose. Par contre, certains états hypolipémiques peu fréquents font maintenant l'objet d'intérêt à cause des conséquences indésirables qu'ils entraînent chez de jeunes malades. L'étude des troubles génétiques du transport des graisses contribue à élucider les mécanismes de manutention intestinale des lipides et du métabolisme des lipoprotéines. Dans cet article, nous revisons brièvement l'état des connaissances au sujet des déficiences héréditaires en lipoprotéines, y compris l'abêtalipoprotéinémie, l'hypobêtalipoprotéinémie et la maladie de rétention des chylomicrons. Ces maladies sont associées à plusieurs charactéristiques communes : malabsorption des graisses, bas niveaux de lipides circulants et de vitamines liposolubles, défaut de croissance en bas âge, neuropathie ataxique et troubles visuels. Par contre, leurs étiologies génétiques sont différentes : l'abêtalipoprotéinémie est causée par l'absence de la protéine de transfert microsomiale, tandis que l'hypobêtalipoprotéinémie est due à des anomalies du gène de l'apolipoprotéine B. Quant à la maladie de rétention des chylomicrons, son étiologie demeure inexpliquée. La recherche au sujet de ces rares maladies héréditaires de l'absorption des graisses va continuer de faire progresser les connaissances de la physiologie humaine et pourrait conduire à des approches nouvelles au traitement de l'athérosclérose.

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Introduction

Plasma lipoproteins are macromolecular complexes that permit the transport of lipids to the circulation for their eventual delivery to other tissues. Lipoproteins are assembled in two organs, the small intestine and the liver, depending on the origin of the lipids.[1,2] Alimentary fat, processed by digestive mechanisms, is absorbed and packaged into chylomicrons by enterocytes,[3] and hepatic lipids originating in the blood stream and from de-novo synthesis are transported by very-low-density lipoproteins (VLDLs).[4] The protein components of plasma lipoproteins are known as apolipoproteins; these contribute to the structural stabilization of the lipoprotein particle, interact with cell-surface receptors and function as powerful activators of plasma enzyme activity.[1­6] The biosynthesis of apolipoproteins is a principal determinant of plasma lipoprotein levels, and defects in their synthesis or function affect lipoprotein metabolism.[7,8] Biochemical, molecular and cell biological studies of various congenital lipid transport disorders have significantly increased our understanding of the role of apolipoproteins. The main aim of this review is to summarize current knowledge of these rare genetic diseases of lipid transport, which have provided insights into the formation and secretion of lipoproteins.

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Intestinal lipoproteins

Traditionally, lipoproteins isolated from fasting plasma by ultracentrifugation are categorized into four classes:[9,10] VLDLs, intermediate-density lipoproteins (IDL), low-density lipoproteins (LDL) and high-density lipoproteins (HDL). Each class of particles has a characteristic distribution of lipids and apolipoproteins (Table 1). The ingestion of lipids induces the intestinal synthesis of chylomicrons, which leave the enterocytes and enter the blood stream via the lymphatic system.[11] Chylomicrons are the main carrier of dietary triglycerides. During a fast, a small proportion of VLDL can also be elaborated from the small intestine.[12] Even HDL, the smallest and most dense lipoprotein, is produced by the small intestine.[13,14] Under certain circumstances, the intestine also produces LDL.[15,16] Studies of jejunal explant cultures from human fetuses and Caco-2 cells, a human intestinal epithelial cell line, have provided evidence that the intestine is involved in the assembly of nascent LDL.[15­17] Unlike plasma LDL, newly synthesized LDL contains a substantial amount of triglycerides. Similarly, hepatic secretion of triglyceride-rich LDL has been observed in many primate and nonprimate species.[18,19] Further studies are necessary to delineate the intracellular mechanisms and the particular conditions that permit the direct elaboration of LDL without the classic pathway involving conversion of VLDL into LDL by lipoprotein lipase. Such studies should provide a better understanding of the factors that determine LDL production in the presence of marked hypercholesterolemia.[20]

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Intestinal apolipoproteins

Despite their key functions, apolipoproteins constitute only 1% of the weight of chylomicrons, and they reside strategically on the surface of the particles. The species native to the intestine are apolipoprotein (apo) A-I, apo A-IV and apo B.[21­23] Other apolipoproteins, such as apo E and several forms of apo C, join chylomicrons in the circulation (Table 2).[21­23] I will present a brief overview of certain genetic lipoprotein disorders later in this article. These inborn errors of metabolism are helping to improve our understanding of the complex processes involved in lipid and apolipoprotein assembly.

Apo B is crucial to exogenous and endogenous fat transport. Two natural forms are produced by the intestine: apo B-100, which comprises 4536 amino acids, and apo B-48, which comprises 2152 amino acids and is the predominant form.[21] The synthesis of apo B-100 in the fetal intestine decreases during maturation, whereas that of apo B-48 increases.[24] Both apo B glycoproteins are encoded by the same gene, located on chromosome 2.[25,26] The molecular mechanism responsible for this intestinal partitioning is referred to as apo B messenger RNA (mRNA) editing, in which codon 2153 is converted from glutamine (CAA) to what is recognized as a premature stop codon (UAA). The post-transcriptional cytidine deamination of glutamine in the nuclear apo B mRNA is mediated by a multicomponent enzyme complex called apo B mRNA editing component-1 (apobec-1).[27] Studies involving various techniques have demonstrated that normal infants and adults retain the ability to express intestinal apo B-100.[28,29]

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Hypobetalipoproteinemia

Familial hypobetalipoproteinemia is a rare, congenital, dominant disorder of lipoprotein metabolism characterized by low levels of apo-B-carrying lipoproteins.[30] The homozygous form of hypobetalipoproteinemia causes severe hypocholesterolemia,[31] with excessive lipid retention in the small-intestinal enterocytes and complete absence of the postprandial delivery of chylomicrons and VLDLs to the circulation.[30,31] Homozygous patients have fat malabsorption, acanthocytosis, extremely low levels of fat-soluble vitamins, retinitis pigmentosa and neurologic disorders due to vitamin E deficiency.[30,31] Although most of the heterozygous patients have no symptoms, they can also present with signs of fat malabsorption and neurologic abnormalities.[32­36] We recently described an infant with heterozygous hypobetalipoproteinemia who presented with chronic diarrhea, steatorrhea, abnormally delayed evoked potential responses in retinal electrophysiologic studies, low levels of vitamins A and E and of beta-carotene, lipid vacuolization of the villus enterocytes and a notable absence of chylomicrons in the intracellular spaces.[37] Jejunal explants cultured with [3H] leucine showed limited synthesis of triglycerides and apo B. At 1 year of age, the patient's intestinal fat absorption had improved and was accompanied by the presence of chylomicrons in the intercellular spaces as well as enhanced synthesis of lipids and apo B, determined by jejunal biopsy.[37] This unusual case illustrates that heterozygous hypobetalipoproteinemia may present early in life as symptomatic lipid malabsorption. Even at age 10, the patient has persistent subclinical malabsorption of fat-soluble vitamins and a deficiency of essential fatty acids, which necessitate supplementation.

Further studies are needed to understand the transient inability to form apo B in patients with symptomatic heterozygous hypobetalipoproteinemia. Today, more than 25 different truncations of apo B have been identified.[38­42] They produce shifts in the reading frames of transcription and premature stop codons that direct the synthesis of truncated apo B molecules of varying lengths.[43,44] Whereas nonsense and frameshift mutations in exons 29-29 (coding for the carboxyl-terminal 70% of apo B-100) result in the production of truncated apo B species, mutations in the 5' portion of the apo B gene yield no detectable apo B protein.[45] In our study, no apo B variants were detected with the use of analytical SDS-PAGE in the young patient.[37] However, we could not infer that the form of hypobetalipoproteinemia in this family was not due to a mutation in the apolipoprotein gene, since molecular analysis was not carried out. Other investigators have reported that the smallest truncated apo B species described, such as apo B-25 and apo B-29, are not detectable in the lipoproteins or lipoprotein-deficient serum fractions because of their impaired secretion or their rapid clearance.[46,47]

Several pathophysiologic states other than apo B mutations can explain the coexistence of low levels of total cholesterol, LDL-cholesterol and apo B. In 1987, Vega and associates[48] reported a case of hypobetalipoproteinemia in which plasma apo B was detectable and of normal size. Its decreased concentration was due to increased hepatic catabolism secondary to constitutionally enhanced bile-acid synthesis. Other investigators have recently described a familial hypobetalipoproteinemia affecting several members of one family spanning three generations. In this case, linkage analysis showed absence of cosegregation between apo B gene alleles and the hypocholesterolemic phenotype.[49] The investigators concluded that a dominant mutation in a gene other than that for apo B is responsible for the low plasma cholesterol levels.

Animal models have been used to better understand hypocholesterolemic disorders. An apo B-deficient mouse that synthesizes truncated apo B-70 has been created.[50] The mouse has reduced apo B mRNA levels in the intestine and the liver, and decreased plasma concentrations of apo B, cholesterol and triglycerides.[50] The knockout of apo B gene in the mouse results in embyronic death in homozygotes and protection against diet-induced hypercholesterolemia in heterozygotes.[51] A surprising result of these studies was a decrease in HDL cholesterol levels in the mice;[50,51] the mechanism causing this reduction remains unclear. On the other hand, in transgenic mice expressing high levels of human apo B, severe atherosclerotic lesions develop in response to a high-fat diet.[52] Some people have suggested that low cholesterol levels may be associated with an increased risk of disease other than cardiovascular disease[53] and that lowering cholesterol concentrations may be harmful.[54] However, patients with heterozygous hypobetalipoproteinemia have a longer-than-average life expectancy and lower-than-average morbidity and mortality despite low levels of cholesterol.[31,37]

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Abetalipoproteinemia

This disorder, transmitted as an autosomal recessive trait, is characterized by the absence of apo B-containing lipoproteins.[55,56] The clinical features of homozygous hypobetalipoproteinemia, described earlier, are also usually found in abetalipoproteinemia.[56,57] Even levels of the HDL fraction and apo A-I are usually decreased in abetalipoproteinemia.[58] Previous studies showed impairment in either the production or catabolism of apo A-I.[59­61] However, a recent investigation in which 131I-labelled apo A-I and 125I-labelled apo E were injected into two unrelated patients demonstrated that abetalipoproteinemia leads to an increased catabolic rate as well as decreased production of apo A-I.[62]

As mentioned earlier, the biochemical hallmark of abetalipoproteinemia is the striking absence of postprandial chylomicrons, VLDL, IDL and LDL. Given these apparent deficiencies, it was initially suggested that abetalipoproteinemia is associated with a defect in the apo B gene. This hypothesis was supported by histochemical and biochemical studies of jejunal explants from affected patients. Investigators were unable to detect the presence of apo B or its synthesis in intestinal tissue.[63,64] However, subsequent reports indicated that the molecular pathogenesis of abetalipoproteinemia is related neither to the apo B gene nor to the biogenesis of its protein product.[65­68] A breakthrough came with the discovery of microsomal triglyceride-transfer protein (MTP) by Wetterau and associates.[69,70] MTP catalyzes the transport of triglyceride, cholesteryl ester and phosphatidylcholine among membranes. It is found in the lumen of microsomes isolated from the liver and intestinal mucosa. However, it is not detectable in specimens obtained by intestinal biopsy from patients with abetalipoproteinemia.[71] Homozygous frameshift and nonsense mutations were revealed in the genomic sequences of two unrelated subjects.[72] These data suggest that MTP is necessary for the assembly of apo B particles.

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Chylomicron retention (Anderson) disease

This clinical syndrome is similar to that caused by abetalipoproteinemia or hypobetalipoproteinemia in its gastrointestinal manifestations and its effect on growth.[73] In contrast with the apo B disorders, hypocholesterolemia is less severe and fasting triglyceride levels are normal in patients with chylomicron retention disease (Table 3).[73] Plasma levels of apo B, apo A-I, LDL and HDL are decreased. After a meal containing fats, plasma triglyceride and chylomicron levels do not increase significantly.[74] When the biogenesis of chylomicrons has been assessed in jejunal explants, triglycerides and chylomicrons appear to be retained in the tissue and are not secreted into the culture medium,[74] confirming the absence of chylomicrons in the intercellular spaces and lacteals.[73] In contrast with the other disorders, normal apo B synthesis and reduced glycosylation are observed in specimens obtained by intestinal biopsy. No apparent cosegregation with the use of restriction fragment-length polymorphism of the apo B gene nor abnormally sized apo B mRNA are observed.[75] It seems, therefore, that chylomicron secretion is impaired in this syndrome, suggesting the defect likely involves the assembly or delivery of lipoprotein particles.

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Conclusions

Lipoprotein transport is extremely dynamic, involving complex intracellular mechanisms. The intensive study of congenital disorders of intestinal fat transport has considerably advanced our understanding of this area of gastrointestinal physiology, and especially of the multiple steps involved in lipoprotein formation. Understanding the interaction or "talk" among various cell compartments, the role of apo B and other apolipoproteins, and the key function of MTP, has afforded us a more comprehensive picture of exogenous and endogenous fat transport. Yet, despite the impressive recent advances, this process is not yet completely elucidated. Nevertheless, we can predict that improvements in technology, especially those related to molecular biology, and other innovative approaches will resolve the remaining issues at a faster pace.

Acknowledgements

I thank Danielle St-Cyr Huot for typing the manuscript. This work was supported by the Medical Research Council of Canada and by a research scholarship from the Fonds de la recherche en santé du Québec. As well, the publication of this article was supported in part by a grant from the Fonds de la recherche en santé du Québec. I would like to thank Ross Laboratories, Canada, for its sponsorship of the invited speakers' program.

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