LXR and ABCA1 control cholesterol homeostasis in the proximal mouse epididymis in a cell-specific manner

Abstract

This article is available online at http://www.jlr.org tozoa to fully mature cells ( 1 , 2 ). Principal aspects of epididymal transformation include functional maturation, sperm concentration, storage of the spermatozoa in a quiescent state, and removal of degenerating cells. Functional maturation of these spermatozoa requires interaction of sperm with luminal fl uid, whose composition is regulated by absorption and secretion activities of the epididymal epithelium ( 3 ).The sperm plasma membrane is the site of dramatic changes throughout the development of these cells, and, in the epididymis, the remodeling process includes important modifi cations in lipid composition as well as repositioning of lipid and protein components to different membrane domains ( 4 ). The lipid composition of mammalian spermatozoa is specifi c with a large amount of plasmalogen phospholipids (PLs), a high content of long-chain PUFAs, mostly arachidonic acid (20:4, n-6), docosapentaenoic acid (22:5, n-3), and docosahexaenoic acid (22:6, n-3), and relatively low cholesterol:PL ratios ranging from 0.24 for caput epididymidis sperm to 0.29 for cauda epididymidis sperm in mice ( 5 ). This ratio is an indicator of membrane fl uidity, and although it is quite stable during epididymal transit, membrane fl uidity was shown to increase during this step ( 6 ). Earlier work showed a significant decrease of the two major PLs, phosphatidylcholine and phosphatidylethanolamine, in mouse spermatozoa from cauda epididymidis compared with those from caput epididymidis ( 5 ). During epididymal maturation, stearic acid (C18:0) decreased also, whereas palmitic acid (C16:0) increased. Among the PUFAs, docosapentaenoic and docosahexaenoic acids rose signifi cantly in the cauda epididymidis. Cholesterol content also declined by roughly 65% during epididymal maturation ( 5 ). These modifi cations have been supposed to prepare sperm cells for capacitation and acrosome reaction that take place in the Abstract Mammalian spermatozoa undergo important plasma membrane maturation steps during epididymal transit. Among these, changes in lipids and cholesterol are of particular interest as they are necessary for fertilization. However, molecular mechanisms regulating these transformations inside the epididymis are still poorly understood. Liver X receptors (LXRs), the nuclear receptors for oxysterols, are of major importance in intracellular cholesterol homeostasis, and LXR ؊ / ؊ -defi cient male mice have already been shown to have reduced fertility at an age of 5 months and complete sterility for 9-month-old animals. This sterility phenotype is associated with testes and caput epididymides epithelial defects. The research presented here was aimed at investigating how LXRs act in the male caput epididymidis by analyzing key actors in cholesterol homeostasis. We show that accumulation of cholesteryl esters in LXR The epididymis is an essential organ for reproductive physiology as sperm cells start the process of posttesticular maturation during their transit in this or...

Phosphatidylserine in the brain: Metabolism and function

“…These results suggest that 18:0, 22:6-PC is particularly favored for the conversion to PS in the brain and provide additional evidence that PC is an important substrate for brain PS synthesis in vivo . Furthermore, MALDI-imaging mass spectrometry studies of mouse brain indicate that 18:0, 22:6-PC is selectively enriched in Purkinje neurons [41], suggesting that this substrate also may be an important source of PS in the cerebellum.…”

Sterols in spermatogenesis and sperm maturation

“…The epididymis possesses the ability for de novo cholesterol synthesis ( 51 ), or it can import cholesterol from the circulation ( 59 ). Cholesterol might be effl uxed into the epididymal lumen by ABCA1 and ATP-binding cassette sub-family G member 1 (ABCG1) ( 53 ). The principal cells of the epididymis secrete small membranous vesicles known as epididymosomes, which could serve as a source for cholesterol exchange with maturing sperm cells ( 128 ).…”

“…Similar to Sertoli cells, cholesterol traffi cking was shown to involve an LXR-regulated mechanism in the mouse epididymis. Effl ux of cholesterol into the lumen is likely to be mediated by the complementary action of ABCA1 and ABCG1, which are well known LXR targets ( 53 ). It is interesting to note that epididymal epithelial cells use a unique apocrine mode of secretion to produce small membranous vesicles called epididymosomes ( Fig.…”

The maturation of murine spermatozoa membranes within the epididymis, a computational biology perspective

“…ABC transporters are a protein superfamily characterized by the presence of ATP-binding cassette (ABC) domains that are involved in inward and outward transport of a wide variety of substrates such as metabolites, drugs, and lipids. In particular, our analysis demonstrates that the ABC transporters play a key role in epididymal biochemistry of sperm membrane rearrangement [Ouvrier et al 2009;Jones and Cry 2011;Morales et al 2012;Caballero et al 2012;Gregory and Cyr 2014;Palme et al 2014]. They are a superfamily of more than 250 transmembrane proteins characterized by a region that spans about 180 amino acids and contains three highly conserved motifs: the Walker A/P-loop (12 amino acids), a signature motif/ C-loop (5 amino acids), and the Walker B motif (5 amino acids) [George and Jones 2012].…”