TY - JOUR
T1 - Peroxisomes can oxidize medium- and long-chain fatty acids through a pathway involving ABCD3 and HSD17B4
AU - Violante, Sara
AU - Achetib, Nihad
AU - van Roermund, Carlo W.T.
AU - Hagen, Jacob
AU - Dodatko, Tetyana
AU - Vaz, Frédéric M.
AU - Waterham, Hans R.
AU - Chen, Hongjie
AU - Baes, Myriam
AU - Yu, Chunli
AU - Argmann, Carmen A.
AU - Houten, Sander M.
N1 - Funding Information: The authors thank Janet Koster (Academic Medical Center) for providing the ABCD3 plasmid, Ethellyn Panta and Tara Singh (Clinical Biochemical Genetics, Icahn School of Medicine at Mount Sinai) for assistance with the acylcarnitine measurements, Charles L. Hoppel (Case Western Reserve University, Cleveland, OH, USA) for quantification of the C14:1-carnitines, and Benny Das (University of Leuven) for technical assistance. Research reported in this publication was supported by U.S. Natiional Institutes of Health (NIH) National Institute of Diabetes and Digestive and Kidney Diseases Award R01DK113172. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. The authors declare no conflicts of interest. Funding Information: The authors thank Janet Koster (Academic Medical Center) for providing the ABCD3 plasmid, Ethellyn Panta and Tara Singh (Clinical Biochemical Genetics, Icahn School of Medicine at Mount Sinai) for assistance with the acylcarnitine measurements, Charles L. Hoppel (Case Western Reserve University, Cleveland, OH, USA) for quantification of the C14:1‐carnitines, and Benny Das (University of Leuven) for technical assistance. Research reported in this publication was supported by U.S. Natiional Institutes of Health (NIH) National Institute of Diabetes and Digestive and Kidney Diseases Award R01DK113172. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. The authors declare no conflicts of interest. Publisher Copyright: © FASEB
PY - 2019/3/1
Y1 - 2019/3/1
N2 - Peroxisomes are essential organelles for the specialized oxidation of a wide variety of fatty acids, but they are also able to degrade fatty acids that are typically handled by mitochondria. Using a combination of pharmacological inhibition and clustered regularly interspaced short palindromic repeats (CRISPR)-CRISPR associated protein 9 genome editing technology to simultaneously manipulate peroxisomal and mitochondrial fatty acid β-oxidation (FAO) in HEK-293 cells, we identified essential players in the metabolic crosstalk between these organelles. Depletion of carnitine palmitoyltransferase (CPT)2 activity through pharmacological inhibition or knockout (KO) uncovered a significant residual peroxisomal oxidation of lauric and palmitic acid, leading to the production of peroxisomal acylcarnitine intermediates. Generation and analysis of additional single- and double-KO cell lines revealed that the D-bifunctional protein (HSD17B4) and the peroxisomal ABC transporter ABCD3 are essential in peroxisomal oxidation of lauric and palmitic acid. Our results indicate that peroxisomes not only accept acyl-CoAs but can also oxidize acylcarnitines in a similar biochemical pathway. By using an Hsd17b4 KO mouse model, we demonstrated that peroxisomes contribute to the plasma acylcarnitine profile after acute inhibition of CPT2, proving in vivo relevance of this pathway. We summarize that peroxisomal FAO is important when mitochondrial FAO is defective or overloaded.—Violante, S., Achetib, N., van Roermund, C. W. T., Hagen, J., Dodatko, T., Vaz, F. M., Waterham, H. R., Chen, H., Baes, M., Yu, C., Argmann, C. A., Houten, S. M. Peroxisomes can oxidize medium- and long-chain fatty acids through a pathway involving ABCD3 and HSD17B4. FASEB J. 33, 4355–4364 (2019). www.fasebj.org.
AB - Peroxisomes are essential organelles for the specialized oxidation of a wide variety of fatty acids, but they are also able to degrade fatty acids that are typically handled by mitochondria. Using a combination of pharmacological inhibition and clustered regularly interspaced short palindromic repeats (CRISPR)-CRISPR associated protein 9 genome editing technology to simultaneously manipulate peroxisomal and mitochondrial fatty acid β-oxidation (FAO) in HEK-293 cells, we identified essential players in the metabolic crosstalk between these organelles. Depletion of carnitine palmitoyltransferase (CPT)2 activity through pharmacological inhibition or knockout (KO) uncovered a significant residual peroxisomal oxidation of lauric and palmitic acid, leading to the production of peroxisomal acylcarnitine intermediates. Generation and analysis of additional single- and double-KO cell lines revealed that the D-bifunctional protein (HSD17B4) and the peroxisomal ABC transporter ABCD3 are essential in peroxisomal oxidation of lauric and palmitic acid. Our results indicate that peroxisomes not only accept acyl-CoAs but can also oxidize acylcarnitines in a similar biochemical pathway. By using an Hsd17b4 KO mouse model, we demonstrated that peroxisomes contribute to the plasma acylcarnitine profile after acute inhibition of CPT2, proving in vivo relevance of this pathway. We summarize that peroxisomal FAO is important when mitochondrial FAO is defective or overloaded.—Violante, S., Achetib, N., van Roermund, C. W. T., Hagen, J., Dodatko, T., Vaz, F. M., Waterham, H. R., Chen, H., Baes, M., Yu, C., Argmann, C. A., Houten, S. M. Peroxisomes can oxidize medium- and long-chain fatty acids through a pathway involving ABCD3 and HSD17B4. FASEB J. 33, 4355–4364 (2019). www.fasebj.org.
KW - CPT2 deficiency
KW - acylcarnitine
KW - fatty acid oxidation
KW - mitochondria
KW - organellar crosstalk
UR - http://www.scopus.com/inward/record.url?scp=85071854403&partnerID=8YFLogxK
U2 - https://doi.org/10.1096/fj.201801498R
DO - https://doi.org/10.1096/fj.201801498R
M3 - Article
C2 - 30540494
SN - 0892-6638
VL - 33
SP - 4355
EP - 4364
JO - FASEB Journal
JF - FASEB Journal
IS - 3
ER -