Neutral Sphingomyelinase 2 (SMPD3) Deficiency in Mice Causes Chondrodysplasia with Unimpaired Skeletal Mineralization.

SMPD3 deficiency in the neutral sphingomyelinase (Smpd3) mouse results in a novel form of juvenile dwarfism, suggesting smpd3 is a polygenetic determinant of body height. SMPD3 controls homeostasis of the sphingomyelin cycle in the Golgi compartment, essential for membrane remodeling, initiating multiform vesicle formation and transport in the Golgi secretory pathway. Using the unbiased Smpd3 genetic model, this study shows that the perturbed Golgi secretory pathway of chondrocytes of the epiphyseal growth zone leads to dysproteostasis, skeletal growth inhibition, malformation, and chondrodysplasia, but showed unimpaired mineralization in primary and secondary enchondral ossification centers.

Novel CB1-ligands maintain homeostasis of the endocannabinoid system in ω3- and ω6-long-chain-PUFA deficiency.

Mammalian ω3- and ω6-PUFAs are synthesized from essential fatty acids (EFAs) or supplied by the diet. PUFAs are constitutive elements of membrane architecture and precursors of lipid signaling molecules. EFAs and long-chain (LC)-PUFAs are precursors in the synthesis of endocannabinoid ligands of G protein-coupled cannabinoid receptor (CB)1 and CB2 in the endocannabinoid system, which critically regulate energy homeostasis as the metabolic signaling system in hypothalamic neuronal circuits and behavioral parameters.

SMPD3 deficiency perturbs neuronal proteostasis and causes progressive cognitive impairment.

Neutral sphingomyelinase smpd3 is most abundantly expressed in neurons of brain. The function of SMPD3 has remained elusive. Here, we report a pathogenetic nexus between absence of SMPD3 in the Golgi compartment (GC) of neurons of the smpd3-/- mouse brain, inhibition of Golgi vesicular protein transport and progressive cognitive impairment.

Hair Growth Cycle Is Arrested in SCD1 Deficiency by Impaired Wnt3a-Palmitoleoylation and Retrieved by the Artificial Lipid Barrier.

Stearoyl-CoA desaturase 1 (SCD1) is the dominant member of the SCD-isozyme family, regarded as a major regulator of lipid and energy metabolism in liver and adipose tissue. SCD1 deficiency impairs the desaturation of de novo-synthesized palmitoyl- and stearoyl-CoA to palmitoleoyl- and oleoyl-CoA. Scd1 mice develop metabolic waste syndrome and skin lesions: epidermal barrier disruption, alopecia, and degeneration of sebaceous glands.

Obesity resistance and deregulation of lipogenesis in Δ6-fatty acid desaturase (FADS2) deficiency.

Δ-6-fatty acid desaturase (FADS2) is the key enzyme in the biosynthesis of polyunsaturated fatty acids (PUFAs), the essential structural determinants of mammalian membrane lipid-bilayers. We developed the auxotrophic fads2(-/-) mouse mutant to assess the enigmatic role of ω3- and ω6-PUFAs in lipid homeostasis, membrane structure and function. Obesity resistance is another major phenotype of the fads2(-/-) mutant, the molecular basis of which is unknown.

Delta6-desaturase (FADS2) deficiency unveils the role of omega3- and omega6-polyunsaturated fatty acids.

Mammalian cell viability is dependent on the supply of the essential fatty acids (EFAs) linoleic and alpha-linolenic acid. EFAs are converted into omega3- and omega6-polyunsaturated fatty acids (PUFAs), which are essential constituents of membrane phospholipids and precursors of eicosanoids, anandamide and docosanoids. Whether EFAs, PUFAs and eicosanoids are essential for cell viability has remained elusive.

Neutral sphingomyelinase (SMPD3) deficiency causes a novel form of chondrodysplasia and dwarfism that is rescued by Col2A1-driven smpd3 transgene expression.

Neutral sphingomyelinase SMPD3 (nSMase2), a sphingomyelin phosphodiesterase, resides in the Golgi apparatus and is ubiquitously expressed. Gene ablation of smpd3 causes a generalized prolongation of the cell cycle that leads to late embryonic and juvenile hypoplasia because of the SMPD3 deficiency in hypothalamic neurosecretory neurons. We show here that this novel form of combined pituitary hormone deficiency is characterized by the perturbation of the hypothalamus-pituitary growth axis, associated with retarded chondrocyte development and enchondral ossification in the epiphyseal growth plate.

Obesity resistance of the stearoyl-CoA desaturase-deficient (scd1-/-) mouse results from disruption of the epidermal lipid barrier and adaptive thermoregulation.

Targeted deletion of the stearoyl-CoA desaturase 1 gene (scd1) in mouse causes obesity resistance and a severe skin phenotype. Here, we demonstrate that SCD1 deficiency disrupts the epidermal lipid barrier and leads to uncontrolled transepidermal water loss, breakdown of adaptive thermoregulation and cold resistance, as well as a metabolic wasting syndrome. The loss of omega-hydroxylated very long-chain fatty acids (VLCFA) and ceramides substituted with omega-hydroxylated VLCFA covalently linked to corneocyte surface proteins leads to the disruption of the epidermal lipid barrier in scd1-/- mutants.

Neutral sphingomyelinase 2 (smpd3) in the control of postnatal growth and development.

Neutral sphingomyelinases sphingomyelin phosphodiesterase (SMPD)2 and -3 hydrolyze sphingomyelin to phosphocholine and ceramide. smpd2 is expressed ubiquitously, and smpd3 is expressed predominantly in neurons of the CNS. Their activation and the functions of the released ceramides have been associated with signaling pathways in cell growth, differentiation, and apoptosis.