Disease relevance of Hsd17b4

• Inactivation of peroxisomal beta-oxidation in mice, by knocking out multifunctional protein-2 (MFP-2; also called d-bifunctional enzyme), causes male infertility [1].
• Interestingly, the immature C27-bile acids in DBP and double knock-out mice remained unconjugated in juvenile mice, whereas they occurred as taurine conjugates after weaning, probably contributing to the minimal weight gain of the mice during the lactation period [2].
• In humans, mutations inactivating multifunctional protein-2 (MFP-2), and thus peroxisomal beta-oxidation, cause neuronal heterotopia and demyelination, which is clinically reflected by hypotonia, seizures, and death within the first year of life [3].
• In contrast to peroxisomes in normal cells, remnant peroxisomes in cultured skin fibroblasts from a subset of the clinically severe peroxisomal disorders that includes the biogenesis disorder Zellweger syndrome and the single-enzyme defect D-bifunctional protein (D-BP) deficiency, are enlarged and significantly less abundant [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

• Previous studies with mice deleted for the Dbp gene have established that DBP participates in the regulation of several clock outputs, including locomotor activity, sleep distribution, and liver gene expression [6].

High impact information on Hsd17b4

• DBP, the founding member of the PAR leucine zipper transcription factor family, is expressed according to a robust daily rhythm in the suprachiasmatic nucleus and several peripheral tissues [6].
• These data indicate that MFP-2 deficiency in mice causes a neurological phenotype in adulthood that is manifested primarily by astroglial damage [3].
• Peroxisomal multifunctional protein-2 deficiency causes motor deficits and glial lesions in the adult central nervous system [3].
• Bile acid biosynthesis, estimated by the ratio of C27/C24-bile acids, was more severely affected in double knock-out mice as compared with DBP-/- mice but was normal in LBP-/- mice [2].
• These changes correlated with a severe impairment of peroxisomal beta-oxidation of very long straight chain fatty acids (C(24)), 2-methyl-branched chain fatty acids, and the bile acid intermediate trihydroxycoprostanic acid in fibroblast cultures or liver homogenates derived from the MFP-2 knockout mice [7].

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 [8].

Biological context of Hsd17b4

• Peroxisomal multifunctional protein 2 is essential for lipid homeostasis in sertoli cells and male fertility in mice [1].
• In contrast, peroxisomal beta-oxidation of long straight chain fatty acids (C(16)) was enhanced in liver tissue from MFP-2(-/-) mice, due to the up-regulation of the enzymes of the classical peroxisomal beta-oxidation pathway [7].
• Amino acid sequence alignment of the 2-enoyl-CoA hydratase 2 domain in human MFE-2 with other MFE-2s reveals conserved protic residues: Tyr-347, Glu-366, Asp-370, His-406, Glu-408, Tyr-410, Asp-490, Tyr-505, Asp-510, His-515, Asp-517, and His-532 [9].
• We investigated the ability of two phthalate esters di-(2-ethylhexyl) phthalate (DEHP) and di-n-butyl phthalate (DBP) and selected metabolites to activate PPAR (alpha, beta/delta, gamma) using a transient transfection assay [10].

Anatomical context of Hsd17b4

• Immunoreactivity for peroxisomal proteins, including MFP-2, was detected in Sertoli cells as well as in germ cells and Leydig cells [1].
• Beta-oxidation of acyl-CoAs 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 [9].
• 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].
• Generation of macrophage activating factor requires a precursor protein, serum vitamin D binding protein (DBP), and participation of lyso-Pc-inducible beta-galactosidase of B lymphocytes [11].
• Interestingly, MFP-2 also fuses with a high efficiency to peripheral blood lymphocytes [12].

Associations of Hsd17b4 with chemical compounds

• Furthermore, MFP-2-deficient mice accumulated VLCFA in brain and liver phospholipids, immature C(27) bile acids in bile, and, after supplementation with phytol, pristanic and phytanic acid in liver triacylglycerols [7].
• As has been shown previously, perMFE-2 hydrates (24E)-3alpha,7alpha, 12alpha-trihydroxy-5beta-cholest-24-enoyl-CoA to (24R, 25R)-3alpha, 7alpha,12alpha,24xi-tetrahydroxy-5beta-choles tanoyl-CoA, which has been characterized as a physiological intermediate in cholic acid synthesis [13].
• DBP, but not the primary metabolite mono-n-butyl phthalate weakly activated all three PPAR subtypes [10].
• Chronic exposure to the PP WY-14,643 (WY) and gemfibrozil (GEM), but not di-n-butyl phthalate (DBP), led to decreases in ES-4 in male rat livers [14].
• Both DEHP and DBP activated expression of PP-inducible gene products in wild-type but not PPARalpha-null mice suggesting that both of these phthalates exert their effects by activation of PPARalpha in vivo [10].

Other interactions of Hsd17b4

• The testicular defects were also present in double MFP-2/peroxisome proliferator-activated receptor-alpha knockout mice, ruling out the possibility that they were mediated through the activation of this nuclear receptor [1].

Analytical, diagnostic and therapeutic context of Hsd17b4

• Human peroxisomal multifunctional enzyme type 2. Site-directed mutagenesis studies show the importance of two protic residues for 2-enoyl-CoA hydratase 2 activity [9].

References