Peroxisomes can oxidize medium‐ and long‐chain fatty acids through a pathway involving ABCD3 and HSD17B4

Abstract

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). http://www.fasebj.org

Peroxisomes in Immune Response and Inflammation

“…The B cells show an intermediary level of both ABCD1 and ABCD2 and in T cells, the level of ABCD1 is very low and ABCD2 is higher. Of note, the ABCD3 gene, which is associated with peroxisomal transport of medium-, long-, branched-chain fatty acids, and bile acid precursors [52,53], is equally expressed in the above described cells. Interestingly, in B cells and in T cells, the ABCD1 deficiency is compensated by the higher expression of ABCD2 [51].…”

Label-Free Proteomics of the Fetal Pancreas Identifies Deficits in the Peroxisome in Rats with Intrauterine Growth Restriction

“…The ABC transporter (Abcd3/Pmp70) is an integral membrane protein involved in the transport of fatty acids across the peroxisomal membrane. Hsd17b4, a D-bifunctional protein, catalyzes the second step of peroxisomal FAO and leads to the formation of a chain-shortened acyl-CoA and acetyl-CoA [19]. It also acts as a catalyst for the formation of 3-ketoacyl-CoA intermediates from both straight-chain and 2-methyl-branched-chain fatty acids.…”

Peroxisomal Metabolite and Cofactor Transport in Humans

“…Under normal conditions, peroxisomal beta-oxidation is the exclusive route for the oxidation of VLCFAs, long-branched chain fatty acids and dicarboxylic acids, and mitochondrial fatty acid beta-oxidation the major route for oxidation of short-, medium-, and long-chain fatty acids in humans. However, when mitochondrial beta-oxidation is compromised, as in the mitochondrial beta-oxidation deficiencies, peroxisomal fatty acid oxidation may serve as an alternative route for the oxidation of short-, medium-, and long-chain fatty acids ( Violante et al, 2013 , 2018 ). This was shown elegantly by combining a defective mitochondrial fatty acid oxidation, generated by introducing a CPT1A deletion or by adding a CPT1 inhibitor, with a defective peroxisomal beta-oxidation, generated by disrupting the gene coding for PEX13 , essential for peroxisome biogenesis.…”