Tyrosine phosphatase SHP2 regulates the expression of acyl-CoA synthetase ACSL4

Abstract

This article is available online at http://www.jlr.org substrate preferences, enzyme kinetics, cellular and organelle locations, and regulation. ACSL4 has a marked preference for 20:4 (arachidonic acid, AA) and 20:5 (eicosapentaenoic acid). The high affi nity of ACSL4 for these fatty acids and the low affi nity for palmitic acid suggest that the enzyme plays a key role in the metabolism of AA. A second interesting feature of ACSL4 is its tissue distribution. In rats, its mRNA is expressed in various tissues, including the adrenal gland, epididymis, brain, lung, ovary, placenta, liver, and testis ( 6, 7 ). The striking feature of ACSL4 is its abundance in steroidogenic tissues, especially in zona fasciculata and reticularis of the rat adrenal gland, Leydig cells of the testis, and luteinized cells of the ovary ( 7 ). It is interesting that although relatively low or null expression levels of ACSL4 have been reported in other adult tissues ( 6, 7 ), this isoform is overexpressed in breast, prostate, colon, and liver cancer specimens ( 8-10 ).Regarding its function , ACSL4 is related to the acute regulation of steroid production in steroidogenic tissues. ACSL4 is a key protein ( 11 ) that works in concert with a mitochondrial acyl-CoA thioesterase, ACOT2 ( 12, 13 ). These two fatty acid-metabolizing enzymes constitute an AA generation/export system, which releases AA in the mitochondrion after the action of the steroidogenic hormones adrenocorticotropin hormone (ACTH) and luteinizing hormone (LH)/ chorionic gonadotropin (CG) ( 14 ). AA is then metabolized to lipoxygenated or epoxygenated products to induce the expression of the steroidogenesis acute regulatory (StAR) gene. StAR is a mitochondrial protein that, together with other proteins, participates in cholesterol transport to the inner mitochondrial membrane, which constitutes the rate-limiting Abstract Acyl-CoA synthetase 4 (ACSL4) is implicated in fatty acid metabolism with marked preference for arachidonic acid (AA). ACSL4 plays crucial roles in physiological functions such as steroid synthesis and in pathological processes such as tumorigenesis. However, factors regulating ACSL4 mRNA and/or protein levels are not fully described. Because ACSL4 protein expression requires tyrosine phosphatase activity, in this study we aimed to identify the tyrosine phosphatase involved in ACSL4 expression. NSC87877, a specifi c inhibitor of the tyrosine phosphatase SHP2, reduced ACSL4 protein levels in ACSL4-rich breast cancer cells and steroidogenic cells. Indeed, overexpression of an active form of SHP2 increased ACSL4 protein levels in MA-10 Leydig steroidogenic cells. SHP2 has to be activated through a cAMP-dependent pathway to exert its effect on ACSL4. The effects could be specifi cally attributed to SHP2 because knockdown of the phosphatase reduced ACSL4 mRNA and protein levels. Through the action on ACSL4 protein levels, SHP2 affected AA-CoA production and metabolism and, fi nally, the steroidogenic capacity of MA-10 cells: overexpression (or knockdown) of SHP2 led ...

The role of mitochondrial fusion and StAR phosphorylation in the regulation of StAR activity and steroidogenesis

“…Through the action on ACSL4 protein levels, SHP2 affects arachidonoyl-CoA (AA-CoA) production and metabolism and, finally, the steroidogenic capacity of MA-10 cells: overexpression (or knockdown) of SHP2 leads to increased (or decreased) steroid production (Cooke et al, 2011). Moreover, SHP2 is needed for the correct association of ERK with mitochondria, as an indirect way of controlling StAR phosphorylation by ERK activity (Duarte et al, 2012).…”

Polymorphisms of PTPN11 gene could influence serum lipid levels in a sex-specific pattern

“…SHP2 could regulate the apoB (apolipoprotein B) secretion in insulin-dependent pattern via phosphatidylinositol 3′-kinase [9,10]. SHP2 activity was associated with the expression of the fatty acid-metabolizing enzyme Acyl-CoA synthetase 4 (ACSL4) [11] and the synthesis of steroid [12]. SHP2 deletion mice could develop a profile of higher serum levels of cholesterol, TG, and low-density lipoprotein [8].…”

Human MicroRNA-548p Decreases Hepatic Apolipoprotein B Secretion and Lipid Synthesis

“…HMGCR is a rate-limiting enzyme in cholesterol synthesis (48). ACSL4 plays a role in fatty acid and triglyceride synthesis (49, 50). Thus, miR-548p may target HMGCR and ACSL4 to reduce lipid synthesis.…”