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February 2011

Ceramide enhances cholesterol efflux to apolipoprotein A-I by increasing the cell surface presence of ATP-binding cassette transporter A1.

It is widely accepted that functional ATP-binding cassette transporter A1 (ABCA1) is critical for the formation of nascent high density lipoprotein particles. However, the cholesterol pool(s) and the cellular signaling processes utilized by the ABCA1-mediated pathway remain unclear. Sphingomyelin maintains a preferential interaction with cholesterol in membranes, and its catabolites, especially ceramide, are potent signaling molecules that could play a role in ABCA1 regulation or function. To study the potential role of ceramide in this process, we treated a variety of cell lines with 20 microM C2-ceramide and examined apolipoprotein-mediated cholesterol efflux to lipid-free apoA-I. We found that cell lines expressing ABCA1 displayed 2-3-fold increases in cholesterol efflux to apoA-I. Cell lines not expressing ABCA1 were unaffected by ceramide. We further characterized the cholesterol efflux effect in Chinese hamster ovary cells. Ceramide treatment did not cause significant cytotoxicity or apoptosis and did not affect cholesterol efflux to non-apolipoprotein acceptors. Raising endogenous ceramide levels increased cholesterol efflux to apoA-I. Using a cell surface biotinylation method, we found that the total cellular ABCA1 and that at the plasma membrane were increased with ceramide treatment. Also ceramide enhanced the binding of fluorescently labeled apoA-I to Chinese hamster ovary cells. These data suggest that ceramide may increase the plasma membrane content of ABCA1, leading to increased apoA-I binding and cholesterol efflux.

J Biol Chem. 2003 Oct 10;278(41):40121-7

Adiponectin in insulin resistance: lessons from translational research.

Adiponectin is an adipose tissue-secreted endogenous insulin sensitizer, which plays a key role as a mediator of peroxisome proliferator-activated receptor gamma action. Adiponectin alters glucose metabolism and insulin sensitivity, exhibits antiinflammatory and antiatherogenic properties, and has been linked to several malignancies. Circulating concentrations of adiponectin are determined primarily by genetic factors, nutrition, exercise, and abdominal adiposity. Adiponectin concentrations are lower in subjects with obesity, metabolic syndrome, and cardiovascular disease. Adiponectin knockout mice manifest glucose intolerance, insulin resistance, and hyperlipidemia and tend to develop malignancies especially when on high-fat diets. Animal studies have also shown beneficial effects of adiponectin in rodents in vivo. Circulating concentrations of adiponectin are lower in patients with diabetes, cardiovascular disease, and several malignancies. Studies to date provide promising results for the diagnostic and therapeutic role of adiponectin in obesity, insulin resistance, diabetes, cardiovascular disease, and obesity-associated malignancies.

Am J Clin Nutr. 2010 Jan;91(1):258S-261S

Adiponectin: a biomarker of obesity-induced insulin resistance in adipose tissue and beyond.

Adiponectin is one of the most thoroughly studied adipocytokines. Low plasma levels of adiponectin are found to associate with obesity, metabolic syndrome, diabetes and many other human diseases. From animal experiments and human studies, adiponectin has been shown to be a key regulator of insulin sensitivity. In this article, we review the evidence and propose that hypo-adiponectinemia is not a major cause of obesity. Instead, it is the result of obesity-induced insulin resistance in the adipose tissue. Hypo-adiponectinemia then mediates the metabolic effects of obesity on the other peripheral tissues, such as liver and skeletal muscle and may also exert some direct effects on end-organ damage. We propose that deciphering the molecular details governing the adiponectin gene expression and protein secretion will lead us to more comprehensive understanding of the mechanisms of insulin resistance in the adipose tissue and provide us new avenues for the therapeutic intervention of obesity and insulin resistance-related human disorders.

J Biomed Sci. 2008 Sep;15(5):565-76

Signal transduction of stress via ceramide.

The sphingomyelin (SM) pathway is a ubiquitous, evolutionarily conserved signalling system analogous to conventional systems such as the cAMP and phosphoinositide pathways. Ceramide, which serves as second messenger in this pathway, is generated from SM by the action of a neutral or acidic SMase, or by de novo synthesis co-ordinated through the enzyme ceramide synthase. A number of direct targets for ceramide action have now been identified, including ceramide-activated protein kinase, ceramide-activated protein phosphatase and protein kinase Czeta, which couple the SM pathway to well defined intracellular signalling cascades. The SM pathway induces differentiation, proliferation or growth arrest, depending on the cell type. Very often, however, the outcome of signalling through this pathway is apoptosis. Mammalian systems respond to diverse stresses with ceramide generation, and recent studies show that yeast manifest a form of this response. Thus ceramide signalling is an older stress response system than the caspase/apoptotic death pathway, and hence these two pathways must have become linked later in evolution. Signalling of the stress response through ceramide appears to play a role in the development of human diseases, including ischaemia/reperfusion injury, insulin resistance and diabetes, atherogenesis, septic shock and ovarian failure. Further, ceramide signalling mediates the therapeutic effects of chemotherapy and radiation in some cells. An understanding of the mechanisms by which ceramide regulates physiological and pathological events in specific cells may provide new targets for pharmacological intervention.

Biochem J. 1998 Nov 1;335 ( Pt 3):465-80

Frictional properties of human forearm and vulvar skin: influence of age and correlation with transepidermal water loss and capacitance.

The dynamic friction coefficient between skin and a Teflon probe and its correlation with age, body weight, height, transepidermal water loss and skin capacitance was studied in vulvar and forearm skin of 44 healthy female volunteers. The friction coefficient of vulvar skin was 0.66 +/- 0.03 (mean +/- SEM) compared to that of forearm skin of 0.48 +/- 0.01. The difference was highly significant (p less than 0.001). Multiple-regression analysis showed that the vulvar skin friction coefficient was significantly correlated with capacitance as an indicator of stratum corneum hydration (p less than 0.01) but not with age, weight, height or transepidermal water loss. It is concluded that the high friction coefficient of vulvar skin may be due to the increased hydration of vulvar skin. Age-related differences seem to exist for transepidermal water loss and friction coefficient in forearm but not in vulvar skin.

Dermatologica. 1990;181(2):88-91

Changes with age in the moisture content of human skin.

A technique to measure the dynamic mechanical properties of human skin in vivo is described. The technique measures the propagation and attenuation of shear waves in skin tissue over a range of frequencies (8-1016 Hz). Results show that both the propagation velocity and attenuation of shear waves in skin are highly dependent upon the water content of the stratum corneum. The technique was used to measure the dynamic mechanical properties of the skin on the back of the left hand for a group of 16 men ranging in age from 24-63 years. The results suggest that aged skin has a lower water content than the skin of younger men.

J Invest Dermatol. 1984 Jan;82(1):97-100

The moisturizing effect of a wheat extract food supplement on women’s skin: a randomized, double-blind placebo-controlled trial.

Ceramides, specific lipid components of the skin, represent 35-40% of the intercellular cement binding cells together and contributing to skin hydration. A wheat extract rich in ceramides and digalactosyl-diglycerides was developed by Hitex in two forms: wheat extract oil (WEO) and wheat extract powder (WEP). In vitro tests and two clinical studies demonstrated promising efficacy results with WEP on skin hydration. To confirm these early results, a double-blind, randomized, placebo-controlled study was carried out on 51 women aged mg of WEO or years with dry to very dry skin who received either 350 20-63 months. Evaluation of skin hydration on legs, arms and face, placebo for 3 assessed at baseline (D0) and at study end (D84) was performed by the dermatologist using dermatological scores (dryness, roughness, erythema), skin hydration measurement (corneometry) and self-assessment scores (Visual Analogue Scale: VAS). Perceived efficacy was noted by participants throughout the study; tolerability and overall acceptability of the study products were evaluated by the dermatologist and the participants at the end of study. Skin hydration was significantly increased between D0 and D84 on the arms (P<0.001) and legs 0.012) in the WEO group compared with placebo. Even if no significant = (P statistical differences between groups were observed for the dermatological evaluation, skin dryness and redness tended to be reduced in the WEO group. Moreover, from D0 to D84, the VAS index had a tendency to increase in favour of 0.084) indicating that participants = WEO for the overall skin hydration (P perceived an improvement. The WEO capsules were perceived by participants as being more effective than placebo on all skin dryness signs. In conclusion, WEO months’ treatment, a capsules were well tolerated and appreciated. After 3 significant increase in skin hydration and an improvement in associated clinical signs were observed in women with dry skin.

Int J Cosmet Sci. 2010 Jul 14

Staphylococcus aureus colonization in atopic dermatitis and its therapeutic implications.

Skin colonization with Staphylococcus aureus is a characteristic feature of atopic dermatitis with more than 90% of patients being colonized. Extracellular matrix proteins are important for the adherence of S. aureus to human keratinocytes. The bacterium interferes in the inflammatory process of atopic dermatitis in various ways, among which the ability to release superantigens in a high percentage of clinical isolates is of great importance. As the colonization correlates significantly with the severity of eczema, anti-staphylococcal treatment measurements are widely used. In cases of atopic dermatitis exacerbation with wide-spread weeping lesions, a systemic antibiotic treatment is warranted, with erythromycin no longer being recommended due to an increased resistance rate. In localized superinfected lesions the topical application of an antibiotic-glucocorticoid preparation may offer advantages to the mere steroid application. Based on efficacy and resistance data, fusidic acid is the antibiotic of choice. There is evidence that phototherapy in atopic dermatitis may be even more effective when combined with anti-staphylococcal measurements. In the future new therapeutical options may be available.

Br J Dermatol. 1998 Dec;139 Suppl 53:13-6

Decreased levels of sphingosine, a natural antimicrobial agent, may be associated with vulnerability of the stratum corneum from patients with atopic dermatitis to colonization by Staphylococcus aureus.

The stratum corneum of the skin of patients with atopic dermatitis is highly susceptible to colonization by various bacteria, including Staphylococcus aureus. The defense system of the skin against bacterial invasion appears to be significantly disrupted in atopic dermatitis skin, but little is known about the defense mechanism(s) involved. As one sphingolipid metabolite, sphingosine is known to exert a potent antimicrobial effect on S. aureus at physiologic levels, and it may play a significant role in bacterial defense mechanisms of healthy normal skin. Because of the altered ceramide metabolism in atopic dermatitis, the possible alteration of sphingosine metabolism might be associated with the acquired vulnerability to colonization by S. aureus in patients with atopic dermatitis. In this study, we measured the levels of sphingosine in the upper stratum corneum from patients with atopic dermatitis, and then compared that with the colonization levels of bacteria in the same subjects. Levels of sphingosine were significantly downregulated in uninvolved and in involved stratum corneum of patients with atopic dermatitis compared with healthy controls. This decreased level of sphingosine was relevant to the increased numbers of bacteria including S. aureus present in the upper stratum corneum from the same subjects. This suggests the possibility that the increased colonization of bacteria found in patients with atopic dermatitis may result from a deficiency of sphingosine as a natural antimicrobial agent. As for the mechanism involved in the decreased production of sphingosine in atopic dermatitis, analysis of the activities of ceramidases, major sphingosine-producing enzymes, revealed that, whereas the activity of alkaline ceramidase did not differ between patients with atopic dermatitis and healthy controls, the activity of acid ceramidase was significantly reduced in patients with atopic dermatitis and this had obvious relevance to the increased colonization of bacteria in those subjects. Further, there was a close correlation between the level of sphingosines and acid ceramidase (r = 0.65, p < 0.01) or ceramides (r = 0.70, p < 0.01) in the upper stratum corneum from the same patients with atopic dermatitis. Collectively, our results suggest the possibility that vulnerability to bacterial colonization in the skin of patients with atopic dermatitis is associated with reduced levels of a natural antimicrobial agent, sphingosine, which results from decreased levels of ceramides as a substrate and from diminished activities of its metabolic enzyme, acid ceramidase.

J Invest Dermatol. 2002 Aug;119(2):433-9

Bacteria and the skin: clinical practice and therapy update.

Any doctor using antibiotics should be aware of the increasing worldwide problem with multiresistant bacteria, with the majority of hospital-based infections in some countries being caused by these bacteria. Proper use of antibiotics is therefore mandatory for any physician, including for dermatologists, who treat bacterial infections of the skin. Detailed knowledge is needed of when to use topical versus systemic antibiotics, and for how long such treatments should be given. Besides the clinical symptoms of bacterial infections and treatment guidelines, an increased awareness has focused on the possible importance of bacterial toxins, including superantigens, and their contribution to skin inflammation. Rare syndromes such as Kawasaki’s syndrome, toxic epidermal necrolysis or staphylococcal scalded skin syndrome, are well-known diseases elicited by specific bacterial toxins. But many observations give indirect support to the notion that bacteriae can augment the immune inflammation seen in common and important diseases such as psoriasis and atopic dermatitis. This supplement provides up-to-date information about skin bacteriology, information on the possible importance of superantigens for chronic skin diseases, and practical guidelines for the use of both topical and systemic antibiotic therapy, together with a review of the dangers following improper use. This information is important for all doctors, including dermatologists.

Br J Dermatol. 1998 Dec;139 Suppl 53:1-3