Lipid composition determines thermotropic properties of meibum of animals and humans with Meibomian gland disorders.

Meibum - a lipid-rich secretion produced by holocrine Meibomian glands (MG) - plays a central role in maintaining ocular surface homeostasis. Previously, changes in MG lipidomes induced by inactivation of critical genes of meibogenesis, such as and others, were shown to cause MG-dysfunction- and dry eye-like signs in mice. Here, we describe the impact of the lipid composition of meibum on its physiological properties, specifically thermotropic/melting characteristics, using various wild type and mutant animals, and compare them with meibum of healthy humans and patients with abnormal meibum.

Abnormal meibum is associated with mutation and IFAP syndrome 2.

The X-linked Ichthyosis Follicularis, Alopecia, and Photophobia syndrome type 2 (IFAP2), is a condition that has been linked to an Arg527-to-Cys mutation in the gene. However, the molecular implications of the mutation in Meibomian glands remained unknown. Our goals were to elucidate the biochemical factors associated with the disease, and allow for unbiased diagnoses of the condition.

Comparative Analysis of Age-Associated Changes in Meibum Composition, Distribution, and Function in Mice With Altered Hyaluronan Expression.

Purpose: Mice lacking hyaluronan (HA) synthase 1 and 3 (Has1-/-; Has3-/- mice) are resistant to meibomian gland (MG) atrophy and dropout. Herein, we characterized the composition and distribution of meibum in Has1-/-; Has3-/- mice as they age and verified whether they are protected from developing dry eye disease (DED).

Methods: Tarsal plates from wild-type (wt) and Has1-/-; Has3-/- mice were isolated, and meibum lipid composition and the distribution of meibum were analyzed by liquid chromatography-mass spectrometry and whole-mount Sudan IV staining, respectively.

Biosynthesis of fatty aldehydes and alcohols in the eye and their role in meibogenesis.

Fatty alcohols (FAlc) and aldehydes (FAld) are essential intermediates/precursors in the biosynthesis of lipids. However, elevated FAld levels were shown to be geno- and cytotoxic, thus requiring conversion into less toxic FAlc and fatty acids (FA). An increase in FAlc and FAld in tissues of patients with Sjögren-Larsson syndrome was reported before and repeatedly linked to inactivation of ALDH3A2, which oxidizes FAld in FA.

Physiological Effects of Soat1 Inactivation on Homeostasis of the Mouse Ocular Surface.

Purpose: Soat1/SOAT1 have been previously reported to be critical for the biosynthesis of cholesteryl esters (CEs) in the mouse Meibomian glands (MGs) as the loss of function led to an arrest of CE production and a substantial accumulation of nonesterified cholesterol in the meibum, causing an increase in its melting temperature. The purpose of this study was to further investigate the role of Soat1 in meibogenesis and ocular surface physiology.

Methods: The mouse ocular features of knockout Soat1-/- and wild type (WT) mice were studied using various ophthalmic and histological techniques, mouse lipidomes were monitored using liquid chromatography/mass spectrometry, whereas their transcriptomes were compared to characterize the effects of the mutation on the gene expression profiles in the MG and cornea.

Comparative Characterization of Human Meibomian Glands, Free Sebaceous Glands, and Hair-Associated Sebaceous Glands Based on Biomarkers, Analysis of Secretion Composition, and Gland Morphology.

Meibomian gland dysfunction (MGD) is one of the main causes of dry eye disease. To better understand the physiological functions of human meibomian glands (MGs), the present study compared MGs with free sebaceous glands (SGs) and hair-associated SGs of humans using morphological, immunohistochemical, and liquid chromatography-mass spectrometry (LCMS)-based lipidomic approaches. Eyelids with MGs, nostrils, lips, and external auditory canals with free SGs, and scalp with hair-associated SGs of body donors were probed with antibodies against cytokeratins (CK) 1, 8, 10, and 14, stem cell markers keratin 15 and N-cadherin, cell-cell contact markers desmoglein 1 (Dsg1), desmocollin 3 (Dsc3), desmoplakin (Dp), plakoglobin (Pg), and E-cadherin, and the tight junction protein claudin 5.

Dysregulation of Lipid Metabolism in Aging Meibomian Glands and Its Molecular Markers.

The main function of exocrine Meibomian glands (MGs) is to produce a lipid-rich secretion called meibum which plays a critical role in maintaining the ocular surface homeostasis of humans and most mammals. The chemical composition of meibum, and its quantity produced by MGs, largely determine whether it can fulfill its role successfully. Aging was frequently associated with the onset of various MG-related pathologies.

Comparative Biophysical Study of Meibomian Lipids of Wild Type and Soat1-Null Mice: Implications to Meibomian Gland Dysfunction and Dry Eye Disease.

Purpose: The biophysical roles of Meibomian lipids (MLs) played in health and meibomian gland dysfunction (MGD) are still unclear. The purpose of this research is to establish the composition-structure-functional correlations of the ML film (MLF) using Soat1-null mice and comprehensive in vitro biophysical simulations.

Methods: MLs were extracted from tarsal plates of wild type (WT) and Soat1 knockout (KO) mice.

Forward genetic screening using fundus spot scale identifies an essential role for Lipe in murine retinal homeostasis.

Microglia play a role in the pathogenesis of many retinal diseases. Fundus spots in mice often correlate with the accumulation of activated subretinal microglia. Here we use a semiquantitative fundus spot scoring scale in combination with an unbiased, state-of-the-science forward genetics pipeline to identify causative associations between chemically induced mutations and fundus spot phenotypes.

Sdr16c5 and Sdr16c6 control a dormant pathway at a bifurcation point between meibogenesis and sebogenesis.

Genes Sdr16c5 and Sdr16c6 encode proteins that belong to a superfamily of short-chain dehydrogenases/reductases (SDR16C5 and SDR16C6). Simultaneous inactivation of these genes in double-KO (DKO) mice was previously shown to result in a marked enlargement of the mouse Meibomian glands (MGs) and sebaceous glands, respectively. However, the exact roles of SDRs in physiology and biochemistry of MGs and sebaceous glands have not been established yet.

Primary cilia control cellular patterning of Meibomian glands during morphogenesis but not lipid composition.

Meibomian glands (MGs) are modified sebaceous glands producing the tear film's lipids. Despite their critical role in maintaining clear vision, the mechanisms underlying MG morphogenesis in development and disease remain obscure. Cilia-mediate signals are critical for the development of skin adnexa, including sebaceous glands.

Probing dietary triacylglycerol metabolism and meibogenesis in mice: A stable isotope-labeled tracer liquid chromatography-tandem mass spectrometry study.

Exocrine meibomian glands (MGs) play a central role in the ocular physiology and biochemistry by producing in situ and, mostly, de novo a secretion (meibum), which is composed of a complex mixture of homologous lipids of various classes, in a metabolic pathway termed meibogenesis. Recent in vivo experiments with a number of mouse models demonstrated that inactivation of any of the major genes of meibogenesis led to alterations in the lipid composition of meibum and severe ocular and MG abnormalities that replicated various human ocular pathologies. However, the role of dietary lipids in meibogenesis, and in the onset and/or alleviation of these diseases, remains controversial.

Dynamic Changes in the Gene Expression Patterns and Lipid Profiles in the Developing and Maturing Meibomian Glands.

Meibomian glands (MGs) and their holocrine secretion-meibum-play crucial roles in the physiology of the eye, providing protection from environmental factors and desiccation, among other functions. Importantly, aging was implicated in the deterioration of the morphology and functions of MGs, and the quantity and quality of meibum they produce, leading to a loss of its protective properties, while the meibum of young individuals and experimental animals provide ample protection to the eye. Currently, the molecular mechanisms of meibum biosynthesis (termed meibogenesis) are not fully understood.

Novel Lipids of the Rabbit Harderian Gland Improve Tear Stability in an Animal Model of Dry Eye Disease.

Instability of the tear film leads to evaporative dry eye disease (EDED), but the Harderian gland in some terrestrial vertebrates may produce novel lipids that stabilize the tear film and protect against dry eye. Here, the nonpolar lipids in the Harderian gland and tears of the rabbit but absent in human tears were identified and tested in preclinical studies to determine whether they could treat severe EDED. Lipids were identified primarily by atmospheric pressure chemical ionization mass spectrometry (MS) and fragmentation MS/MS.

Effects of Aging on Human Meibum.

Purpose: The purpose of this study was to determine if aging affects meibum lipid composition in non-meibomian gland dysfunction (MGD)/non-dry eye (DE) population. Aging has been repeatedly linked to pathological changes in various tissues and organs, including the onset of MGD and DE, in a number of clinical and population-wide surveys. Both conditions have been associated with abnormal meibum secretion and composition, among other factors.

Differential effects of dietary cholesterol and triglycerides on the lipid homeostasis in Meibomian glands.

Exocrine Meibomian glands (MG) play a central role in the ocular surface physiology by producing meibum - a lipid secretion composed of cholesteryl esters (CE), cholesterol (Chl), triacylgycerols (TAG), waxes and other types of lipids. MG were previously shown to synthesize Meibomian lipids (ML) in situ via a complex array of reactions termed meibogenesis. However, questions remain about the role of dietary lipids in meibogenesis.

Depletion of Cholesteryl Esters Causes Meibomian Gland Dysfunction-Like Symptoms in a -Null Mouse Model.

Previous studies on ablation of several key genes of meibogenesis related to fatty acid elongation, omega oxidation, and esterification into wax esters have demonstrated that inactivation of any of them led to predicted changes in the meibum lipid profiles and caused severe abnormalities in the ocular surface and Meibomian gland (MG) physiology and morphology. In this study, we evaluated the effects of ablation that were expected to cause depletion of the second largest class of Meibomian lipids (ML)-cholesteryl esters (CE)-in a mouse model. ML of the null mice were examined using liquid chromatography high-resolution mass spectrometry and compared with those of and wild-type mice.

Comprehensive profiling of Asian and Caucasian meibomian gland secretions reveals similar lipidomic signatures regardless of ethnicity.

Meibum-a lipid secretion that is produced by Meibomian glands (MG) in a process termed meibogenesis-plays a critical role in ocular surface physiology. Abnormalities in the chemical composition of meibum were linked to widespread ocular pathologies-dry eye syndrome (DES) and MG dysfunction (MGD). Importantly, in epidemiologic studies the Asian population was shown to be prone to these pathologies more than the Caucasian one, which was tied to differences in their meibomian lipids.

Delineating a novel metabolic high triglycerides-low waxes syndrome that affects lipid homeostasis in meibomian and sebaceous glands.

Meibomian glands that are embedded in tarsal plates of human eyelids, and sebaceous glands found in the skin, including that of eyelids, are two related types of holocrine glands that produce lipid-rich secretions called meibum and sebum. Pervasive ocular disorders, such as Meibomian gland dysfunction and dry eye, have been linked to changes in the lipid composition of meibum. However, in most described cases the changes were either small, or random, or insufficiently characterized on the molecular level.

Comparative Transcriptomic and Lipidomic Analyses of Human Male and Female Meibomian Glands Reveal Common Signature Genes of Meibogenesis.

Meibum is a lipid secretion that is produced by holocrine Meibomian glands (MGs). MGs are a specialized type of sebaceous glands that are embedded in the human eyelids. Chemically, meibum and sebum are different.

On the pivotal role of /ELOVL3 in meibogenesis and ocular physiology of mice.

The purpose of this study was to examine the role of gene in meibogenesis and the impact of ELOVL3 protein ablation on the physiology of the mouse ocular surface and Meibomian glands (MGs). knockout, ELOVL3-ablated () mice and their wild type littermates () were studied side by side. mice had abnormal ocular phenotypes such as delayed eye opening, weeping eyes, crusty eyelids, eyelid edema, highly vascularized cornea and tarsal plates (TPs), slit eye, and increased tearing that resemble symptoms observed in human subjects with various forms of dry eye, MG dysfunction and blepharitis.

Cyclic Change of Fatty Acid Composition in Meibum During the Menstrual Cycle.

Purpose: To evaluate the fatty acid (FA) composition in the meibum of pre- and postmenopausal women and age-matched men.

Methods: This prospective study involved 24 healthy subjects; six premenopausal women in their 30s with a regular menstrual cycle (young-female [yF] group), six postmenopausal women in their 60s (elderly-female [eF] group), and 12 age-matched men (i.e.

Effects of sex (or lack thereof) on meibogenesis in mice (Mus musculus): Comparative evaluation of lipidomes and transcriptomes of male and female tarsal plates.

The possible role of sex in the biosynthesis of lipids in the Meibomian glands (termed meibogenesis) remains unclear. To determine if there were any major sex-specific differences in the lipid composition of meibomian gland secretions (meibum) and gene expression patterns (GEP) related to meibogenesis, we conducted a study using healthy, age and diet-matched young adult wild-type C57BL/6J mice (2-2.5 month old).

Meibomian glands, meibum, and meibogenesis.

Meibum is a lipid-rich secretion that is produced by fully differentiated meibocytes in the holocrine Meibomian glands (MG) of humans and most mammals. The secretion is a part of a defense mechanism that protects the ocular surface from hazardous environmental factors, and from desiccation. Meibomian lipids that have been identified in meibum are very diverse and unique in nature.