Murine deficiency of peroxisomal L-bifunctional protein (EHHADH) causes medium-chain 3-hydroxydicarboxylic aciduria and perturbs hepatic cholesterol homeostasis.

Cellular and Molecular Life Sciences : CMLS
Pablo Ranea-RoblesSander M Houten

Abstract

Peroxisomes play an essential role in the β-oxidation of dicarboxylic acids (DCAs), which are metabolites formed upon ω-oxidation of fatty acids. Genetic evidence linking transporters and enzymes to specific DCA β-oxidation steps is generally lacking. Moreover, the physiological functions of DCA metabolism remain largely unknown. In this study, we aimed to characterize the DCA β-oxidation pathway in human cells, and to evaluate the biological role of DCA metabolism using mice deficient in the peroxisomal L-bifunctional protein (Ehhadh KO mice). In vitro experiments using HEK-293 KO cell lines demonstrate that ABCD3 and ACOX1 are essential in DCA β-oxidation, whereas both the bifunctional proteins (EHHADH and HSD17B4) and the thiolases (ACAA1 and SCPx) have overlapping functions and their contribution may depend on expression level. We also show that medium-chain 3-hydroxydicarboxylic aciduria is a prominent feature of EHHADH deficiency in mice most notably upon inhibition of mitochondrial fatty acid oxidation. Using stable isotope tracing methodology, we confirmed that products of peroxisomal DCA β-oxidation can be transported to mitochondria for further metabolism. Finally, we show that, in liver, Ehhadh KO mice have increased...Continue Reading

References

Jan 16, 1976·Clinica Chimica Acta; International Journal of Clinical Chemistry·H PrzyrembelS K Wadman
Dec 16, 1991·Biochemical and Biophysical Research Communications·V J HodgeS K Krisans
Dec 1, 1991·The American Journal of Physiology·S J Jin, K Y Tserng
Jul 1, 1991·Metabolism: Clinical and Experimental·K Y TserngC L Hoppel
Feb 1, 1990·Nature·J L Goldstein, M S Brown
Mar 5, 1991·Biochemistry·K Y Tserng, S J Jin
Dec 18, 1989·Biochimica Et Biophysica Acta·M S Poosch, R K Yamazaki
May 21, 1986·Biochimica Et Biophysica Acta·S Kølvraa, N Gregersen
Sep 15, 1985·The Biochemical Journal·J VamecqF Van Hoof
Nov 1, 1974·Experimental Cell Research·G M Williams, J M Gunn
Apr 1, 1972·Clinica Chimica Acta; International Journal of Clinical Chemistry·J E PettersenL Eldjarn
Mar 28, 1980·Clinica Chimica Acta; International Journal of Clinical Chemistry·N GregersenR Lauritzen
Jan 1, 1995·Journal of Inherited Metabolic Disease·E MayatepekG F Hoffmann
Jan 1, 1994·Journal of Inherited Metabolic Disease·M J BennettA B Burlina
Mar 14, 1998·Clinica Chimica Acta; International Journal of Clinical Chemistry·C Vianey-SabanC Roe
Jul 10, 1998·Clinica Chimica Acta; International Journal of Clinical Chemistry·M FontaineJ Vamecq
Dec 23, 1998·Proceedings of the National Academy of Sciences of the United States of America·D M KurtzP A Wood
Jul 6, 2000·Clinica Chimica Acta; International Journal of Clinical Chemistry·W RöschingerA A Roscher
Oct 24, 2001·The Journal of Biological Chemistry·Mary C HuntStefan E H Alexson
Jun 12, 2003·American Journal of Physiology. Endocrinology and Metabolism·Daniel Z BrunengraberStephen F Previs
May 1, 1960·Toxicology and Applied Pharmacology·I I RUSOFFR THIESSEN
Dec 16, 2003·Molecular and Cellular Biology·Werner J KovacsSkaidrite K Krisans
Jan 20, 2004·Journal of Lipid Research·Sietske HogenboomHans R Waterham
Jan 20, 2004·Journal of Cell Science·Sietske HogenboomHans R Waterham
Aug 17, 2004·Molecular Genetics and Metabolism·Paul S Berger, Philip A Wood
Feb 25, 2005·Toxicological Sciences : an Official Journal of the Society of Toxicology·Marja van de BovenkampPeter Olinga
Sep 6, 2005·The Journal of Biological Chemistry·Maria A K WestinStefan E H Alexson
Oct 4, 2005·Proceedings of the National Academy of Sciences of the United States of America·Aravind SubramanianJill P Mesirov
Jun 8, 2006·Annual Review of Biochemistry·Ronald J A Wanders, Hans R Waterham
Aug 31, 2006·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Mary C HuntStefan E H Alexson
Dec 21, 2006·Histochemistry and Cell Biology·Werner J KovacsSkaidrite K Krisans
Apr 20, 2007·Biochemical and Biophysical Research Communications·Ruud DirkxPaul P Van Veldhoven
Dec 14, 2007·Molecular Genetics and Metabolism·Malika ChegarySander M Houten
Jul 16, 2008·Biochimica Et Biophysica Acta·Su Duy NguyenPaul P Van Veldhoven
Sep 9, 2008·Biochimica Et Biophysica Acta·Katrin MartensMyriam Baes
Dec 31, 2008·The Journal of Biological Chemistry·Ilya R BedermanStephen F Previs

❮ Previous
Next ❯

Citations

Aug 28, 2021·International Journal of Molecular Sciences·Mounia Tahri-JouteyNorbert Latruffe
Sep 27, 2021·Journal of Inherited Metabolic Disease·Pablo Ranea-RoblesSander M Houten

❮ Previous
Next ❯

Software Mentioned

Gene Set Enrichment Analysis ( GSEA )
limma
ImageJ
R
featureCounts
DESeq2
STAR

Related Concepts

Trending Feeds

COVID-19

Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

Blastomycosis

Blastomycosis fungal infections spread through inhaling Blastomyces dermatitidis spores. Discover the latest research on blastomycosis fungal infections here.

Nuclear Pore Complex in ALS/FTD

Alterations in nucleocytoplasmic transport, controlled by the nuclear pore complex, may be involved in the pathomechanism underlying multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Here is the latest research on the nuclear pore complex in ALS and FTD.

Applications of Molecular Barcoding

The concept of molecular barcoding is that each original DNA or RNA molecule is attached to a unique sequence barcode. Sequence reads having different barcodes represent different original molecules, while sequence reads having the same barcode are results of PCR duplication from one original molecule. Discover the latest research on molecular barcoding here.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Evolution of Pluripotency

Pluripotency refers to the ability of a cell to develop into three primary germ cell layers of the embryo. This feed focuses on the mechanisms that underlie the evolution of pluripotency. Here is the latest research.

Position Effect Variegation

Position Effect Variagation occurs when a gene is inactivated due to its positioning near heterochromatic regions within a chromosome. Discover the latest research on Position Effect Variagation here.

STING Receptor Agonists

Stimulator of IFN genes (STING) are a group of transmembrane proteins that are involved in the induction of type I interferon that is important in the innate immune response. The stimulation of STING has been an active area of research in the treatment of cancer and infectious diseases. Here is the latest research on STING receptor agonists.

Microbicide

Microbicides are products that can be applied to vaginal or rectal mucosal surfaces with the goal of preventing, or at least significantly reducing, the transmission of sexually transmitted infections. Here is the latest research on microbicides.