to VLDL and LDL, thus favoring reverse cholesterol t r a n ~ p o r twhereas ,~ adaptation to a high-fat diet favored the movement of cholesterol into cells, suggesting that the unloading of cholesterol from cells is less likely to happen during postprandial lipemia under these conditions. Consequently, this study provides a better understanding of why chronic dietary fat and cholesterol intake is related to coronary disease risk and the potential interaction of postprandial lipemia as a contributing factor. One would conclude from these results that the atherogenicity of lipoprotein particles generated during fat absorption is determined primarily by the previous dietary history of the individual rather than simply by the degree of increase in these triglyceride-rich particles after a meal. In the discussion of their results, the authors provided a very good consideration of the similarities and differences in lipoprotein metabolism between baboons and humans, which contributes to the interpretation of the results. However, it would have been useful to have more detailed in-
formation about the fatty acid composition of the diets, especially in view of the significant effects that fatty acid composition has on postprandial lipemia. Likewise, it will be important to determine in future studies the specific role of dietary fatty acids or cholesterol in mediating these responses. 1. Weintraub MS, Zechner R, Brown A, Eisenberg S, Breslow JL. Dietary polyunsaturated fats of the W-6 and W-3 series reduce postprandial lipoprotein levels. J CLin Invest 1988;82:1884-93 2. Harris WS, Conner WE, Alam N, lllingworth DR. Reduction of postprandial triglyceridemia in humans by dietary n-3 fatty acids. J Lipid Res 1988;29:1451-60 3. Zilversmit DB. Atherogenesis: a postprandial phenomenon. Circulation 1979;60:473-85 4. Brown MS, Goldstein JL. A receptor-mediated pathway for cholesterol homeostasis. Science 1986;232 :34- 7 5. Fielding PE, Jackson EM, Fielding CJ. Chronic dietary fat and cholesterol inhibit the normal postprandial stimulation of plasma cholesterol metabolism. J Lipid Res 1989;30:1211-7 6. Castro GR, Fielding CJ. Effects of postprandial lipemia on plasma cholesterol metabolism. J Clin Invest 1985;75:874-82
BIOTIN IN ANIMAL NUTRITION Recent studies showed that a small but significant amount o f biotin is absorbed in the distal small intestine o f the pig. Although some biotin produced b y the intestinal microflora is utilized b y pigs, they appear to rely on absorption from the proximal small intestine to prevent dermatologic lesions associated with biotin deficiency.
Biotin has long been recognized to have an essential metabolic function in animals and humans, that of the mobile carboxyl carrier in several carboxylase enzymes: the pyruvate, propionyl-coenzyme A (CoA), and 3methylcrotonyl-CoA carboxylases of mitochondria and the acetyl-CoA carboxylase of cytoplasm. Nevertheless, the vitamin has frequently been considered only peripherally in discussions of applied nutrition. Although it is generally recognized that biotin deficiency can be induced by feeding raw egg white, which contains the biotin352 NUTRITION RNlEWSlVOL 48,NO 9ISEPTEMBER 1990
binding protein avidin, spontaneous cases of biotin deficiency have been thought to be rare enough, and biotin distribution in foods and feedstuffs wide enough, to imply that the practical need for the vitamin was readily met by animals and humans consuming mixed diets. This view has changed in recent years, partly because of discoveries (of particular importance in pediatric nutrition) of congenital defects in biotin-dependent enzymes in humans, and because of documentation of spontaneous biotin defi-
ciencies and responses to biotin treatment among livestock (e.g., turkeys, chickens, pigs, fish, and fur-bearing animals) under practical conditions of management. However, despite this revision in thinking, the quantitative needs for biotin in the major species of food animals have continued to be based on a relatively narrow body of data. A comprehensive reevaluation of the role of biotin in swine nutrition was published recently by Kopinski et al.1-5 Unlike many previous investigations in which egg white was fed to induce biotin deficiency, these investigators used a low-biotin, semipurified diet (based on corn flour and casein and containing only 10 Fg of biotinlkg). This approach avoided the potential problems associated with the feeding of egg white (e.g., presence of trypsin inhibitors), thus facilitating the interpretation of the results. Further, they used baby pigs weaned at two days of age to this diet; this removed the influences of milk and maternal feces as potential sources of biotin. The authors undertook to determine the quantitative requirement for biotin of the growing pig,’,* to study the enteric absorption of and to estimate the biologic availability of biotin from various practical feedstuffs for swine.4 Kopinski et al.’ found that deprivation of dietary biotin resulted in dermatologic lesions of the hoof, skin, and tongue. Foot lesions were apparent within 54 days of feeding the diet: deep fissures on the hoof, necrosis along the coronet, extensive sloughing of the heel horn, and hyperplasia of the corium. The accompanying skin lesions were dry and flaky skin, loss of hair from the hams, and the development of brownish encrustations and pustules. In addition, most deficient animals showed oral signs that the authors described as “furry tongue.” Of significance was the finding that, despite these lesions, biot in-def icient an imals showed no impairments in growth rate or efficiency of feed utilization as have been reported to accompany the dermatologic lesions induced by egg white. The authors
proffer two hypotheses for these apparently discrepant results. The first is that egg white-induced growth depression may involve effects other than that of biotin-activation by avidin in that material and that, until very severe depletion of the vitamin is achieved, biotin may not be required for growth. Alternatively, they acknowledge that the biotin available from the small amount in the diet, plus any from microbial biosynthesis in the hind gut, may have been sufficient to meet any needs for the vitamin to support normal growth. Kopinski et a1.l determined that the minimal dietary level required to prevent the dermatologic lesions is 50-100 pg/kg, and that the higher level supported optimal concentrations of biotin in hair and tissues, suggesting tissue saturation.2 It is of interest that that range is the same as currently suggested6s7 on the basis of early work with egg white-fed pigs.8 Kopinski et a1.l found that, although deprivation of the vitamin reduced the biotin concentrations of several soft tissues (by 40-87%) and urine (by 43-91%), it produced no consistent changes in the fecal excretion of the vitamin. Because such a finding can indicate microbial biosynthesis of biotin in the lower gastrointestinal tract, the authors suggested that the nearly normal fecal biotin excretion of pigs showing clinical signs of biotin deficiency indicates that little or no microbially produced biotin is absorbed from the lower gut. However, as the site(s) of enteric biotin absorption in the pig were unknown, Kopinski et al.3.5did studies to determine whether the vitamin can be absorbed from the lower gut. They measured biotin in the lumenal contents of the gut and found it to decline with distance down the proximal half of the small intestine to a concentration of about onethird of that of the diet;3 this finding was taken as evidence of primary absorption of the vitamin. In the distal half, however, the net biotin content increased dramatically; in that portion of the gut, the biotin concentration of the digesta was three- to fourfold higher than that of the diet. This increase, which they surmised to be due NUTRITION REVlEWSlVOL 48, NO 9ISEPTEMBER 1990 353
either to microbial synthesis of the vitamin at that site or to back-flow of digesta from the caeca, precluded detection by this method of postileal absorption of biotin. In order to determine whether appreciable postileal absorption occurred, as has been shown for the rat,g Kopinski et al.5 conducted further studies in which they administered biotin by chronic caecal infusion, or in which they tracked the clearance of single oral or caecal doses of radiolabeled biotin. The continuous infusion of biotin into the caecum over a five-week period was found to produce increases in the biotin contents of selected tissues, a fact suggesting absorption of the biotin from the distal small intestine. However, because those tissue levels were less than those of animals fed similar amounts of the vitamin, the apparent postileal absorption of biotin was taken to be less than that in the proximal small intestine. Kopinski et al.5 then produced direct evidence of postileal absorption. Using a balloon catheter to occlude the ileum proximal to the caeca, they found that radiolabeled biotin administered to the caecal lumen appeared in the urine within 15 min. However, both the size of the plasma [l4C]biotin pool and the amount of [14C]biotin excreted in the urine after a caecal dose of the radiolabeled vitamin were only 8% of those after an oral dose. Therefore, it was concluded that postileal absorption of biotin does, indeed, occur in the pig. While the postileal absorption of biotin appears to be only about 8% as efficient as absorption from the proximal small intestine, that rate may be sufficient, given microbial synthesis of the vitamin at that site, to contribute to the biotin nutrition of the pig (e.g., to support growth, if not to prevent dermatologic lesions). Having found that most of the enteric absorption of biotin occurs in the proximal small intestine of the pig, Kopinski et al.4 undertook to use ileal digestibility of dietary biotin to assess the biologic availability of the vitamin from several practical feedstuffs. They compared results obtained by this method from both pigs and 354 NUTRITION REVIEWSIVOL 48,NO 9ISEPTEMBER 1990
chickens and found a high positive correlation for several feedstuffs. The available biotin from these sources ranged from very low (e.g., wheat) to moderate (e.g., barley, soybean meal) to high (e.g., meat meal, casein). It is curious that both pigs and chickens showed negative biotin digestibility for sorghum. While the physiologic basis for that observation was not clear, Kopinski et aL4 speculated that it may have involved either the formation of unabsorbable biotin complexes, the enhancement of microbial biotin synthesis, or the stimulation of the retrograde flow of digesta from the hind gut into the ileum due to the presence of factor(s) in sorghum. In general, however, this approach appears to be useful in assessing biotin bioavailability in the pig, as approaches useful in other species have proved infeasible in the pig due either to the lack of response (e.g., growth),’ low activity (e.g., pyruvate carboxylase),1° or excessive variation (e.g., plasma biotin concentration).11 Their study4 also showed that several feedstuffs commonly used in feeding swine and poultry in Australia (where these studies were conducted) as well as many other parts of the world are generally poor sources of biologically available biotin. These recent studies by Kopinski et al.1-5 showed that biotin offers interesting problems in animal nutrition today. While it is both widely distributed in feedstuffs and produced microbially in the gut, its utilization from these respective sources can be severely limited because of poor bioavailability and low absorbability.
Kopinski JS, Leibholz J, Bryden W l , Fogarty AC. Biotin studies in pigs. 1. Biotin deficiency in the young pig. Br J Nutr 1989;62:751-9 Kopinski JS, Leibholz J. Biotin studies in pigs. 2. The biotin requirement of the growing pig. Br J Nutr 1989;62:761-6 Kopinski JS, Leibholz J, Bryden WL. Biotin studies in pigs. 3. Biotin absorption and synthesis. Br J Nutr 1989;62:767-72 Kopinski JS, Leibholz J, Bryden WL. Biotin studies in pigs. 4. Biotin availability in feedstuffs for pigs and chickens. Br J Nutr 1989;62:773-80
5.
Kopinski JS, Leibholz J, Love RJ. Biotin studies in pigs. 5. The postileal absorption of biotin. Br J Nutr 1989;62:781-9 6. National Academy of Sciences-National Research Council. Nutrient requirements of domestic animals, no. 2. Nutrient requirements of swine. 9th ed. Washington, DC: National Academy Press, 1988 7. Agricultural Research Council. The nutrient requirements of pigs: technical review. Slough: Commonwealth Agricultural Bureau, 1981 8. Cunha TJ, Smith DA, Irwin VCR. Biotin deficiency
syndrome in pigs fed desiccated egg white. J Anim Sci 1946;5:219-25 9. Bowman BB, Rosenberg IH. Biotin absorption by the distal rat intestine. J Nutr 1987;117:2121-6 10. Whitehead CC, Bannister DW, D’Mello JPF. Blood pyruvate carboxylase activity as a criterion of biotin status in young pigs. Res Vet Sci 1980;29: 126-8 11. Misir R, Blair R. Biotin availability from protein supplements and cereal grains from weanling pigs. Can J Anim Sci 1988;68:523-32
EXPRESSION OF A RETlNOlC ACID-RECEPTOR GENE IS REGULATED BY RETlNOlC ACID ITSELF Two nuclear receptors for retinoic acid (alpha and beta) exist; they have a differential tissue distribution and presumably different physiologic functions. Retinoic acid, by combining with its receptor, up-regulates the expression of the beta but not the alpha retinoic acid receptor gene, pointing to a case of autoregulation of the receptor by its own ligand.
A closely related family of proteins can act as receptors (or binding proteins) of steroid and thyroid hormones (ligands). As a result of ligand binding, these receptors attach to the DNA of a specific gene, resulting in gene activation, followed by its transcription and translation to protein. The latest addition to this family has been the receptor for the active form of vitamin A (retinoic acid or RA). This recognition of gene activation by RA, similar to that of steroid and thyroid hormones, represents a great advance in the understanding of the mechanism of action of vitamin A on growth and differentiation.’** Isolation of a gene that is activated by the retinoic acidretinoic acid receptor complex (RA-RAR) does not, of course, reveal which particular protein will be expressed as a result of this activation. Recently two proteins (growth hormone3p4and laminin5) whose synthesis is stimulated by RA-RAR interaction with the promoter regions of their respective genes have been identified. We now learn
of a third specific protein whose synthesis is up-regulated by the RA-RAR complex. Surprisingly, this is the RAR All these receptors for steroid and thyroid hormones and for RA have two highly conserved, homologous regions in common, the DNA-binding domain and the ligand-binding domain. Recently two different cDNAs with homologies in the DNAbinding domain to RAR were cloned, transcribed, and translated; the result was two different RARs, alpha and beta, with nearly identical DNA- and ligand-binding domains, but otherwise quite different. De The et a1.6 speculated that these two different RARs, when activated by RA and after binding to different genes, can lead to two or more different physiologic roles for RA. Indeed, it was found that these two RARs are activated to 50% of maximal activity by different concentrations of RA M for alpha, M for beta); thus the two RARs have different affinities for RA and ultimately d iffe rent physiologic functions. NUTRITION REVIEWSIVOL 48, NO 9ISEPTEMBER 1990 355
formation about the fatty acid composition of the diets, especially in view of the significant effects that fatty acid composition has on postprandial lipemia. Likewise, it will be important to determine in future studies the specific role of dietary fatty acids or cholesterol in mediating these responses. 1. Weintraub MS, Zechner R, Brown A, Eisenberg S, Breslow JL. Dietary polyunsaturated fats of the W-6 and W-3 series reduce postprandial lipoprotein levels. J CLin Invest 1988;82:1884-93 2. Harris WS, Conner WE, Alam N, lllingworth DR. Reduction of postprandial triglyceridemia in humans by dietary n-3 fatty acids. J Lipid Res 1988;29:1451-60 3. Zilversmit DB. Atherogenesis: a postprandial phenomenon. Circulation 1979;60:473-85 4. Brown MS, Goldstein JL. A receptor-mediated pathway for cholesterol homeostasis. Science 1986;232 :34- 7 5. Fielding PE, Jackson EM, Fielding CJ. Chronic dietary fat and cholesterol inhibit the normal postprandial stimulation of plasma cholesterol metabolism. J Lipid Res 1989;30:1211-7 6. Castro GR, Fielding CJ. Effects of postprandial lipemia on plasma cholesterol metabolism. J Clin Invest 1985;75:874-82
BIOTIN IN ANIMAL NUTRITION Recent studies showed that a small but significant amount o f biotin is absorbed in the distal small intestine o f the pig. Although some biotin produced b y the intestinal microflora is utilized b y pigs, they appear to rely on absorption from the proximal small intestine to prevent dermatologic lesions associated with biotin deficiency.
Biotin has long been recognized to have an essential metabolic function in animals and humans, that of the mobile carboxyl carrier in several carboxylase enzymes: the pyruvate, propionyl-coenzyme A (CoA), and 3methylcrotonyl-CoA carboxylases of mitochondria and the acetyl-CoA carboxylase of cytoplasm. Nevertheless, the vitamin has frequently been considered only peripherally in discussions of applied nutrition. Although it is generally recognized that biotin deficiency can be induced by feeding raw egg white, which contains the biotin352 NUTRITION RNlEWSlVOL 48,NO 9ISEPTEMBER 1990
binding protein avidin, spontaneous cases of biotin deficiency have been thought to be rare enough, and biotin distribution in foods and feedstuffs wide enough, to imply that the practical need for the vitamin was readily met by animals and humans consuming mixed diets. This view has changed in recent years, partly because of discoveries (of particular importance in pediatric nutrition) of congenital defects in biotin-dependent enzymes in humans, and because of documentation of spontaneous biotin defi-
ciencies and responses to biotin treatment among livestock (e.g., turkeys, chickens, pigs, fish, and fur-bearing animals) under practical conditions of management. However, despite this revision in thinking, the quantitative needs for biotin in the major species of food animals have continued to be based on a relatively narrow body of data. A comprehensive reevaluation of the role of biotin in swine nutrition was published recently by Kopinski et al.1-5 Unlike many previous investigations in which egg white was fed to induce biotin deficiency, these investigators used a low-biotin, semipurified diet (based on corn flour and casein and containing only 10 Fg of biotinlkg). This approach avoided the potential problems associated with the feeding of egg white (e.g., presence of trypsin inhibitors), thus facilitating the interpretation of the results. Further, they used baby pigs weaned at two days of age to this diet; this removed the influences of milk and maternal feces as potential sources of biotin. The authors undertook to determine the quantitative requirement for biotin of the growing pig,’,* to study the enteric absorption of and to estimate the biologic availability of biotin from various practical feedstuffs for swine.4 Kopinski et al.’ found that deprivation of dietary biotin resulted in dermatologic lesions of the hoof, skin, and tongue. Foot lesions were apparent within 54 days of feeding the diet: deep fissures on the hoof, necrosis along the coronet, extensive sloughing of the heel horn, and hyperplasia of the corium. The accompanying skin lesions were dry and flaky skin, loss of hair from the hams, and the development of brownish encrustations and pustules. In addition, most deficient animals showed oral signs that the authors described as “furry tongue.” Of significance was the finding that, despite these lesions, biot in-def icient an imals showed no impairments in growth rate or efficiency of feed utilization as have been reported to accompany the dermatologic lesions induced by egg white. The authors
proffer two hypotheses for these apparently discrepant results. The first is that egg white-induced growth depression may involve effects other than that of biotin-activation by avidin in that material and that, until very severe depletion of the vitamin is achieved, biotin may not be required for growth. Alternatively, they acknowledge that the biotin available from the small amount in the diet, plus any from microbial biosynthesis in the hind gut, may have been sufficient to meet any needs for the vitamin to support normal growth. Kopinski et a1.l determined that the minimal dietary level required to prevent the dermatologic lesions is 50-100 pg/kg, and that the higher level supported optimal concentrations of biotin in hair and tissues, suggesting tissue saturation.2 It is of interest that that range is the same as currently suggested6s7 on the basis of early work with egg white-fed pigs.8 Kopinski et a1.l found that, although deprivation of the vitamin reduced the biotin concentrations of several soft tissues (by 40-87%) and urine (by 43-91%), it produced no consistent changes in the fecal excretion of the vitamin. Because such a finding can indicate microbial biosynthesis of biotin in the lower gastrointestinal tract, the authors suggested that the nearly normal fecal biotin excretion of pigs showing clinical signs of biotin deficiency indicates that little or no microbially produced biotin is absorbed from the lower gut. However, as the site(s) of enteric biotin absorption in the pig were unknown, Kopinski et al.3.5did studies to determine whether the vitamin can be absorbed from the lower gut. They measured biotin in the lumenal contents of the gut and found it to decline with distance down the proximal half of the small intestine to a concentration of about onethird of that of the diet;3 this finding was taken as evidence of primary absorption of the vitamin. In the distal half, however, the net biotin content increased dramatically; in that portion of the gut, the biotin concentration of the digesta was three- to fourfold higher than that of the diet. This increase, which they surmised to be due NUTRITION REVlEWSlVOL 48, NO 9ISEPTEMBER 1990 353
either to microbial synthesis of the vitamin at that site or to back-flow of digesta from the caeca, precluded detection by this method of postileal absorption of biotin. In order to determine whether appreciable postileal absorption occurred, as has been shown for the rat,g Kopinski et al.5 conducted further studies in which they administered biotin by chronic caecal infusion, or in which they tracked the clearance of single oral or caecal doses of radiolabeled biotin. The continuous infusion of biotin into the caecum over a five-week period was found to produce increases in the biotin contents of selected tissues, a fact suggesting absorption of the biotin from the distal small intestine. However, because those tissue levels were less than those of animals fed similar amounts of the vitamin, the apparent postileal absorption of biotin was taken to be less than that in the proximal small intestine. Kopinski et al.5 then produced direct evidence of postileal absorption. Using a balloon catheter to occlude the ileum proximal to the caeca, they found that radiolabeled biotin administered to the caecal lumen appeared in the urine within 15 min. However, both the size of the plasma [l4C]biotin pool and the amount of [14C]biotin excreted in the urine after a caecal dose of the radiolabeled vitamin were only 8% of those after an oral dose. Therefore, it was concluded that postileal absorption of biotin does, indeed, occur in the pig. While the postileal absorption of biotin appears to be only about 8% as efficient as absorption from the proximal small intestine, that rate may be sufficient, given microbial synthesis of the vitamin at that site, to contribute to the biotin nutrition of the pig (e.g., to support growth, if not to prevent dermatologic lesions). Having found that most of the enteric absorption of biotin occurs in the proximal small intestine of the pig, Kopinski et al.4 undertook to use ileal digestibility of dietary biotin to assess the biologic availability of the vitamin from several practical feedstuffs. They compared results obtained by this method from both pigs and 354 NUTRITION REVIEWSIVOL 48,NO 9ISEPTEMBER 1990
chickens and found a high positive correlation for several feedstuffs. The available biotin from these sources ranged from very low (e.g., wheat) to moderate (e.g., barley, soybean meal) to high (e.g., meat meal, casein). It is curious that both pigs and chickens showed negative biotin digestibility for sorghum. While the physiologic basis for that observation was not clear, Kopinski et aL4 speculated that it may have involved either the formation of unabsorbable biotin complexes, the enhancement of microbial biotin synthesis, or the stimulation of the retrograde flow of digesta from the hind gut into the ileum due to the presence of factor(s) in sorghum. In general, however, this approach appears to be useful in assessing biotin bioavailability in the pig, as approaches useful in other species have proved infeasible in the pig due either to the lack of response (e.g., growth),’ low activity (e.g., pyruvate carboxylase),1° or excessive variation (e.g., plasma biotin concentration).11 Their study4 also showed that several feedstuffs commonly used in feeding swine and poultry in Australia (where these studies were conducted) as well as many other parts of the world are generally poor sources of biologically available biotin. These recent studies by Kopinski et al.1-5 showed that biotin offers interesting problems in animal nutrition today. While it is both widely distributed in feedstuffs and produced microbially in the gut, its utilization from these respective sources can be severely limited because of poor bioavailability and low absorbability.
Kopinski JS, Leibholz J, Bryden W l , Fogarty AC. Biotin studies in pigs. 1. Biotin deficiency in the young pig. Br J Nutr 1989;62:751-9 Kopinski JS, Leibholz J. Biotin studies in pigs. 2. The biotin requirement of the growing pig. Br J Nutr 1989;62:761-6 Kopinski JS, Leibholz J, Bryden WL. Biotin studies in pigs. 3. Biotin absorption and synthesis. Br J Nutr 1989;62:767-72 Kopinski JS, Leibholz J, Bryden WL. Biotin studies in pigs. 4. Biotin availability in feedstuffs for pigs and chickens. Br J Nutr 1989;62:773-80
5.
Kopinski JS, Leibholz J, Love RJ. Biotin studies in pigs. 5. The postileal absorption of biotin. Br J Nutr 1989;62:781-9 6. National Academy of Sciences-National Research Council. Nutrient requirements of domestic animals, no. 2. Nutrient requirements of swine. 9th ed. Washington, DC: National Academy Press, 1988 7. Agricultural Research Council. The nutrient requirements of pigs: technical review. Slough: Commonwealth Agricultural Bureau, 1981 8. Cunha TJ, Smith DA, Irwin VCR. Biotin deficiency
syndrome in pigs fed desiccated egg white. J Anim Sci 1946;5:219-25 9. Bowman BB, Rosenberg IH. Biotin absorption by the distal rat intestine. J Nutr 1987;117:2121-6 10. Whitehead CC, Bannister DW, D’Mello JPF. Blood pyruvate carboxylase activity as a criterion of biotin status in young pigs. Res Vet Sci 1980;29: 126-8 11. Misir R, Blair R. Biotin availability from protein supplements and cereal grains from weanling pigs. Can J Anim Sci 1988;68:523-32
EXPRESSION OF A RETlNOlC ACID-RECEPTOR GENE IS REGULATED BY RETlNOlC ACID ITSELF Two nuclear receptors for retinoic acid (alpha and beta) exist; they have a differential tissue distribution and presumably different physiologic functions. Retinoic acid, by combining with its receptor, up-regulates the expression of the beta but not the alpha retinoic acid receptor gene, pointing to a case of autoregulation of the receptor by its own ligand.
A closely related family of proteins can act as receptors (or binding proteins) of steroid and thyroid hormones (ligands). As a result of ligand binding, these receptors attach to the DNA of a specific gene, resulting in gene activation, followed by its transcription and translation to protein. The latest addition to this family has been the receptor for the active form of vitamin A (retinoic acid or RA). This recognition of gene activation by RA, similar to that of steroid and thyroid hormones, represents a great advance in the understanding of the mechanism of action of vitamin A on growth and differentiation.’** Isolation of a gene that is activated by the retinoic acidretinoic acid receptor complex (RA-RAR) does not, of course, reveal which particular protein will be expressed as a result of this activation. Recently two proteins (growth hormone3p4and laminin5) whose synthesis is stimulated by RA-RAR interaction with the promoter regions of their respective genes have been identified. We now learn
of a third specific protein whose synthesis is up-regulated by the RA-RAR complex. Surprisingly, this is the RAR All these receptors for steroid and thyroid hormones and for RA have two highly conserved, homologous regions in common, the DNA-binding domain and the ligand-binding domain. Recently two different cDNAs with homologies in the DNAbinding domain to RAR were cloned, transcribed, and translated; the result was two different RARs, alpha and beta, with nearly identical DNA- and ligand-binding domains, but otherwise quite different. De The et a1.6 speculated that these two different RARs, when activated by RA and after binding to different genes, can lead to two or more different physiologic roles for RA. Indeed, it was found that these two RARs are activated to 50% of maximal activity by different concentrations of RA M for alpha, M for beta); thus the two RARs have different affinities for RA and ultimately d iffe rent physiologic functions. NUTRITION REVIEWSIVOL 48, NO 9ISEPTEMBER 1990 355
