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Gene Review

HSD17B4  -  hydroxysteroid (17-beta) dehydrogenase 4

Homo sapiens

Synonyms: 17-beta-HSD 4, 17-beta-hydroxysteroid dehydrogenase 4, D-bifunctional protein, DBP, EDH17B4, ...
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Disease relevance of HSD17B4

  • Patients previously diagnosed as cases of L-bifunctional protein deficiency probably should be reexamined for a possible d-bifunctional protein deficiency [1].
  • METHODS: To improve early recognition, diagnosis, prognosis, and management of this disorder and to provide markers for life expectancy, we performed extensive biochemical studies in a large cohort of D-bifunctional protein-deficient patients and sent out questionnaires about clinical signs and symptoms to the responsible physicians [2].
  • In bivariate analysis, birth weight was positively associated with SBP (beta = 0.87) and DBP (beta = 1.14) in black children (P < 0.001) but not associated with either in white children [3].
  • After 50 weeks of therapy with delapril/manidipine 30mg/10mg once daily, mean SBP/DBP was reduced by 22/14mm Hg in patients with mild to moderate hypertension (n = 309) [4].
  • We previously found that di-butyl phthalate (DBP) has an adjuvant effect in a mouse contact hypersensitivity model, in which fluorescein isothiocyanate (FITC) is involved as an immunogenic hapten [5].

Psychiatry related information on HSD17B4

  • RESULTS: Systolic BP (SBP) was linearly related significantly to BMI and alcohol consumption, whereas diastolic BP (DBP) was related to age [6].
  • The UV/TiO(2)/glass process yielded a 75% degradation efficiency of DBP with initial concentration of 5mgL(-1) at 80min reaction time [7].

High impact information on HSD17B4


Chemical compound and disease context of HSD17B4

  • Phthalate esters with short alkyl chains, such as di-ethyl (DEP), di-n-propyl (DPP), and di-butyl phthalate (DBP), have adjuvant effects on an FITC-induced contact hypersensitivity mouse model [12].

Biological context of HSD17B4

  • The HSD17B4 gene consist of 24 exons and 23 introns with classical intron-exon junctions spanning more than 100 kbp [13].
  • Recombinant human PTS1 binding protein Pex5p interacted with the bacterially expressed C-terminal domain of the HSD17B4 gene product [14].
  • Subsequent mutation analysis showed that both patients are homozygous for a missense mutation (N457Y), which is located in the enoyl-CoA hydratase coding part of the D-bifunctional protein gene [9].
  • A nonfunctional version of MFE2 did not restore normal peroxisome morphology to mfe2-KO cells, indicating that their phenotype is not due to the absence of MFE2. mfe2-KO cells contain higher amounts of beta-oxidation enzymes than do wild-type cells [15].
  • Gly(16) and Gly(329) of the S. cerevisiae A and B domains, corresponding to Gly(16), which is mutated in the human MFE-2 deficiency, were mutated to serine and cloned into the yeast expression plasmid pYE352 [16].

Anatomical context of HSD17B4

  • The HSD17B4 gene codes for a 80 kDa multifunctional enzyme containing three distinct functional domains and is localized in peroxisomes [13].
  • The contents of the L- and D-bifunctional proteins were about 0.01 and 0.5 microg/mg protein, respectively, in cultured human skin fibroblasts [17].
  • Upon sensitization in the presence of DBP or DPP, the number of FITC-positive dendritic cells (total CD11c(+) as well as CD11c(+)/CD11b(+)) was increased in draining lymph nodes [5].
  • Protein kinase C activation therefore appears to dissociate the expression of aromatase and 17 beta-HSD 4 in this differentiation stage along the monocyte/phagocyte pathway of THP 1 myeloid cells [18].
  • CONCLUSIONS: In patients without glaucoma, the DBP <90 mm Hg that results from antihypertensive treatment is associated with increased cupping and decreased rim area of the optic disk [19].

Associations of HSD17B4 with chemical compounds

  • The HSD17B4 gene is stimulated by progesterone, and ligands of PPARalpha (peroxisomal proliferator activated receptor alpha) such as clofibrate, and is down-regulated by phorbol esters [20].
  • Characterization of the HSD17B4 gene: D-specific multifunctional protein 2/17beta-hydroxysteroid dehydrogenase IV [13].
  • beta-Oxidation of amino acyl coenzyme A (acyl-CoA) species in mammalian peroxisomes can occur via either multifunctional enzyme type 1 (MFE-1) or type 2 (MFE-2), both of which catalyze the hydration of trans-2-enoyl-CoA and the dehydrogenation of 3-hydroxyacyl-CoA, but with opposite chiral specificity [21].
  • We propose that, among the reactions of the distinct group of carboxylates oxidized specifically in peroxisomes, oxidation of 2-methyl-branched fatty acids and side-chain shortening of cholesterol for bile acid formation are catalyzed by the D-bifunctional protein, but not the L-bifunctional protein [17].
  • The activity of conversion of hexadecenoyl-CoA to 3-ketopalmitoyl-CoA by the D-bifunctional protein was estimated to be about 0.5 milliunit/mg of fibroblast protein [17].

Enzymatic interactions of HSD17B4


Other interactions of HSD17B4


Analytical, diagnostic and therapeutic context of HSD17B4


  1. D-3-hydroxyacyl-CoA dehydratase/D-3-hydroxyacyl-CoA dehydrogenase bifunctional protein deficiency: a newly identified peroxisomal disorder. Suzuki, Y., Jiang, L.L., Souri, M., Miyazawa, S., Fukuda, S., Zhang, Z., Une, M., Shimozawa, N., Kondo, N., Orii, T., Hashimoto, T. Am. J. Hum. Genet. (1997) [Pubmed]
  2. Clinical and biochemical spectrum of D-bifunctional protein deficiency. Ferdinandusse, S., Denis, S., Mooyer, P.A., Dekker, C., Duran, M., Soorani-Lunsing, R.J., Boltshauser, E., Macaya, A., Gärtner, J., Majoie, C.B., Barth, P.G., Wanders, R.J., Poll-The, B.T. Ann. Neurol. (2006) [Pubmed]
  3. Racial disparities in the association between birth weight in the term infant and blood pressure at age 7 years: results from the collaborative perinatal project. Hemachandra, A.H., Klebanoff, M.A., Furth, S.L. J. Am. Soc. Nephrol. (2006) [Pubmed]
  4. Delapril/manidipine. McCormack, P.L., Keating, G.M. Drugs (2006) [Pubmed]
  5. Effects of phthalate esters on the sensitization phase of contact hypersensitivity induced by fluorescein isothiocyanate. Imai, Y., Kondo, A., Iizuka, H., Maruyama, T., Kurohane, K. Clin. Exp. Allergy (2006) [Pubmed]
  6. Is high job strain associated with hypertension genesis? Ducher, M., Cerutti, C., Chatellier, G., Fauvel, J.P. Am. J. Hypertens. (2006) [Pubmed]
  7. Degradation of di-n-butyl phthalate using photoreactor packed with TiO(2) immobilized on glass beads. Chiou, C.S., Shie, J.L., Chang, C.Y., Liu, C.C., Chang, C.T. J. Hazard. Mater. (2006) [Pubmed]
  8. Peroxisomal D-hydroxyacyl-CoA dehydrogenase deficiency: resolution of the enzyme defect and its molecular basis in bifunctional protein deficiency. van Grunsven, E.G., van Berkel, E., Ijlst, L., Vreken, P., de Klerk, J.B., Adamski, J., Lemonde, H., Clayton, P.T., Cuebas, D.A., Wanders, R.J. Proc. Natl. Acad. Sci. U.S.A. (1998) [Pubmed]
  9. Enoyl-CoA hydratase deficiency: identification of a new type of D-bifunctional protein deficiency. van Grunsven, E.G., Mooijer, P.A., Aubourg, P., Wanders, R.J. Hum. Mol. Genet. (1999) [Pubmed]
  10. Breast cancer DNA methylation profiles in cancer cells and tumor stroma: association with HER-2/neu status in primary breast cancer. Fiegl, H., Millinger, S., Goebel, G., Müller-Holzner, E., Marth, C., Laird, P.W., Widschwendter, M. Cancer Res. (2006) [Pubmed]
  11. Peroxisomal straight-chain Acyl-CoA oxidase and D-bifunctional protein are essential for the retroconversion step in docosahexaenoic acid synthesis. Su, H.M., Moser, A.B., Moser, H.W., Watkins, P.A. J. Biol. Chem. (2001) [Pubmed]
  12. Effects of phthalate esters on dendritic cell subsets and interleukin-4 production in fluorescein isothiocyanate-induced contact hypersensitivity. Maruyama, T., Shiba, T., Iizuka, H., Matsuda, T., Kurohane, K., Imai, Y. Microbiol. Immunol. (2007) [Pubmed]
  13. Characterization of the HSD17B4 gene: D-specific multifunctional protein 2/17beta-hydroxysteroid dehydrogenase IV. Möller, G., Leenders, F., van Grunsven, E.G., Dolez, V., Qualmann, B., Kessels, M.M., Markus, M., Krazeisen, A., Husen, B., Wanders, R.J., de Launoit, Y., Adamski, J. J. Steroid Biochem. Mol. Biol. (1999) [Pubmed]
  14. Peroxisome targeting of porcine 17beta-hydroxysteroid dehydrogenase type IV/D-specific multifunctional protein 2 is mediated by its C-terminal tripeptide AKI. Möller, G., Lüders, J., Markus, M., Husen, B., Van Veldhoven, P.P., Adamski, J. J. Cell. Biochem. (1999) [Pubmed]
  15. Regulation of peroxisome size and number by fatty acid beta -oxidation in the yeast yarrowia lipolytica. Smith, J.J., Brown, T.W., Eitzen, G.A., Rachubinski, R.A. J. Biol. Chem. (2000) [Pubmed]
  16. Yeast peroxisomal multifunctional enzyme: (3R)-hydroxyacyl-CoA dehydrogenase domains A and B are required for optimal growth on oleic acid. Qin, Y.M., Marttila, M.S., Haapalainen, A.M., Siivari, K.M., Glumoff, T., Hiltunen, J.K. J. Biol. Chem. (1999) [Pubmed]
  17. Physiological role of D-3-hydroxyacyl-CoA dehydratase/D-3-hydroxyacyl-CoA dehydrogenase bifunctional protein. Jiang, L.L., Kurosawa, T., Sato, M., Suzuki, Y., Hashimoto, T. J. Biochem. (1997) [Pubmed]
  18. Expression and regulation of aromatase and 17 beta-hydroxysteroid dehydrogenase type 4 in human THP 1 leukemia cells. Jakob, F., Homann, D., Adamski, J. J. Steroid Biochem. Mol. Biol. (1995) [Pubmed]
  19. Association of blood pressure status with the optic disk structure in non-glaucoma subjects: the Thessaloniki eye study. Topouzis, F., Coleman, A.L., Harris, A., Jonescu-Cuypers, C., Yu, F., Mavroudis, L., Anastasopoulos, E., Pappas, T., Koskosas, A., Wilson, M.R. Am. J. Ophthalmol. (2006) [Pubmed]
  20. Unique multifunctional HSD17B4 gene product: 17beta-hydroxysteroid dehydrogenase 4 and D-3-hydroxyacyl-coenzyme A dehydrogenase/hydratase involved in Zellweger syndrome. de Launoit, Y., Adamski, J. J. Mol. Endocrinol. (1999) [Pubmed]
  21. Crystal structure of the liganded SCP-2-like domain of human peroxisomal multifunctional enzyme type 2 at 1.75 A resolution. Haapalainen, A.M., van Aalten, D.M., Meriläinen, G., Jalonen, J.E., Pirilä, P., Wierenga, R.K., Hiltunen, J.K., Glumoff, T. J. Mol. Biol. (2001) [Pubmed]
  22. Sensitive analysis of serum 3alpha, 7alpha, 12alpha,24-tetrahydroxy- 5beta-cholestan-26-oic acid diastereomers using gas chromatography-mass spectrometry and its application in peroxisomal D-bifunctional protein deficiency. Vreken, P., van Rooij, A., Denis, S., van Grunsven, E.G., Cuebas, D.A., Wanders, R.J. J. Lipid Res. (1998) [Pubmed]
  23. Radical production and cytotoxic activity of tert-butyl-substituted phenols. Saito, M., Atsumi, T., Satoh, K., Ishihara, M., Iwakura, I., Sakagami, H., Yokoe, I., Fujisawa, S. In vitro & molecular toxicology. (2001) [Pubmed]
  24. A variety of environmentally persistent chemicals, including some phthalate plasticizers, are weakly estrogenic. Jobling, S., Reynolds, T., White, R., Parker, M.G., Sumpter, J.P. Environ. Health Perspect. (1995) [Pubmed]
  25. Twenty-Four-Hour Ambulatory BP in Snoring Children With Obstructive Sleep Apnea Syndrome. Leung, L.C., Ng, D.K., Lau, M.W., Chan, C.H., Kwok, K.L., Chow, P.Y., Cheung, J.M. Chest (2006) [Pubmed]
  26. Molecular analysis of genomic DNA allows rapid, and accurate, prenatal diagnosis of peroxisomal D-bifunctional protein deficiency. Paton, B.C., Solly, P.B., Nelson, P.V., Pollard, A.N., Sharp, P.C., Fietz, M.J. Prenat. Diagn. (2002) [Pubmed]
  27. Vitamin D-binding protein (DBP) gene polymorphism is associated with Graves' disease and the vitamin D status in a Polish population study. Kurylowicz, A., Ramos-Lopez, E., Bednarczuk, T., Badenhoop, K. Exp. Clin. Endocrinol. Diabetes (2006) [Pubmed]
  28. Bile acid profiles in a peroxisomal D-3-hydroxyacyl-CoA dehydratase/D-3-hydroxyacyl-CoA dehydrogenase bifunctional protein deficiency. Une, M., Konishi, M., Suzuki, Y., Akaboshi, S., Yoshii, M., Kuramoto, T., Fujimura, K. J. Biochem. (1997) [Pubmed]
  29. Dietary and lifestyle factors associated with blood pressure among U.S. adolescents. Sugiyama, T., Xie, D., Graham-Maar, R.C., Inoue, K., Kobayashi, Y., Stettler, N. The Journal of adolescent health : official publication of the Society for Adolescent Medicine (2007) [Pubmed]
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