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Purpose of Review: Genome-wide association studies identified ORMDL3, a protein of the endoplasmic reticulum, as a significant asthma risk factor. ORMDL3 is one of three ORMDL proteins that integrate multiple signals to maintain sphingolipid homeostasis. Studies that investigated potential mechanisms for how increased ORMDL3 might affect asthma are summarized., Recent Findings: Investigations focused on decreased sphingolipid synthesis and on the unfolded protein response because ORMDL3 had been implicated in both.Airway reactivity is increased in a genetic model with decreased de-novo sphingolipid synthesis and in wild-type mice treated with myriocin, a sphingolipid synthesis inhibitor. Inflammation, mucus production and airway smooth muscle hypertrophy are absent. ORMDL3 was not evaluated directly but results suggest that decreased sphingolipid synthesis is sufficient to induce airway hyperreactivity (AHR).Direct effects of ORMDL3 were investigated in allergic asthma models. Sensitization with ovalbumin, house dust mites and Alternaria alternata increase ORMDL3 mRNA. Universal overexpression of ORMDL3 decreases serum sphingolipids, increases inflammatory markers, airway remodeling and AHR in response to allergic stimuli. Addition of myriocin during sensitization drastically exacerbates house dust mites-induced AHR.ORMDL3 knockout mice are protected from developing A. alternata-induced AHR. The effect is specific to Alternaria and limited to smooth muscle contraction, as inflammation persists. ORMDL3 might have a critical role for smooth muscle contraction.Little is known about how the different ORMDL3 single nucleotide polymorphisms affect human blood and tissue sphingolipid profiles. One group measured total sphingoid levels and found no association with ORMDL3 single nucleotide polymorphisms in a general population. Others evaluated sphingolipid profiles in 7-8-year old children with mild asthma and found significantly higher C18 and C20 ceramides in those with persistence of asthma symptoms 3 years later, suggesting that sphingolipid profiles might predict asthma persistence., Summary: Possible mechanisms how ORMDL3 affects asthma include inhibition of sphingolipid synthesis, synergistic effects with known allergens and a combination of both.

Purpose of Review: Expression of defective cystic fibrosis transmembrane conductance regulator (CFTR), the cause for cystic fibrosis, affects fatty acid, cholesterol and sphingolipid metabolism. This review summarizes recent observations and evaluates current understanding of mechanisms., Recent Findings: Recent observations implicate CFTR, in addition to known effects on fatty acid and cholesterol metabolism, in the regulation of sphingolipid metabolism and suggest that this pathway is relevant to inflammation and infection. A common mechanism on how CFTR affects such a wide spectrum of lipid classes is currently not known. One mechanism for low linoleic acid, amenable to inhibition by docosahexaenoic acid, is increased metabolism in the n-6 fatty acid pathway. Accumulation of free cholesterol in distinct perinuclear compartments, reversible by overexpression of rab9, suggests that cystic fibrosis and the lysosomal storage disease Niemann-Pick-C could share similar cell signaling defects, in addition to increased cAMP signaling and sterol-regulatory element binding protein (SREBP) expression that affect cholesterol metabolism. Novel is the recognition that CFTR modulates ceramide mass and uptake of sphingosine-1- phosphate. Experiments in different cystic fibrosis-mouse models, although not able to establish whether ceramide mass is increased or decreased, suggest that normalization of ceramide decreases infection and selected parameters of inflammation, of relevance to the complex phenotype that characterizes cystic fibrosis., Summary: Expression of defective CFTR has profound effects on fatty acid, cholesterol and sphingolipid metabolism, for which mechanisms are currently poorly understood. Recent studies in different cystic fibrosis models suggest a causal relationship between altered ceramide mass and increased inflammation and susceptibility to infection. Studies in cystic fibrosis knockout mouse models suggest that normalization of ceramide decreases infection and inflammation. Studies that evaluate the diagnostic and clinical relevance of sphingolipids in patients with cystic fibrosis are needed.

Purpose of Review: Sphingolipids and their metabolites regulate a great variety of cellular processes. Recent findings implicate sphingolipids in the regulation of lipid synthesis, lipoprotein metabolism and the development of atherosclerosis., Recent Findings: Sphingolipid synthesis correlates with the regulation of the sterol-regulatory element-binding proteins - key transcription factors of genes of lipid metabolism. Inhibition of sphingolipid synthesis decreases synthesis of genes regulated by sterol regulatory element-binding protein, such as the rate-limiting enzymes of fatty acid and cholesterol synthesis as well as fatty-acyl-CoA synthases, important in the synthesis of phospholipids. In animal models, inhibition of sphingolipid synthesis correlates with decreased atherosclerotic lesions and a decreased susceptibility of lipoproteins to aggregate--a key mechanism in the development of the atherosclerotic lesion. The demonstration that ceramide and glucosylceramide (metabolites of sphingolipid synthesis) affect cholesterol efflux and mechanisms that regulate plasma high-density lipoprotein concentrations is further evidence for a role of sphingolipids in the regulation of lipid homeostasis. Direct mechanisms of how sphingolipid synthesis regulates lipid synthesis are currently unknown. The recent identification of key proteins of synthesis and specific transport proteins that regulate sphingolipid synthesis, however, is expected to contribute to the understanding about the interdependent regulation of sphingolipid and lipid metabolism., Summary: Emerging data strongly suggest a role of sphingolipid synthesis in the regulation of transcription factors and regulatory proteins that control cellular lipid homeostasis.

Fatty acids are a major constituent of dietary fats and form an integral part of the cellular membrane and lipoproteins. The gene regulatory potential of fatty acids has long been recognized, but the precise regulatory mechanisms are unknown. The regulatory ability of fatty acids on the expression of a number of genes together with potential mechanisms and pathways of regulation are reviewed. In this review, we emphasize a key aspect of regulation mediated by the sterol regulatory element binding-protein, and its effects on sterol regulatory elements.