Reactivation of PPARα alleviates myocardial lipid accumulation and cardiac dysfunction by improving fatty acid β-oxidation in Dsg2-deficient arrhythmogenic cardiomyopathy

Arrhythmogenic cardiomyopathy (ACM), a fatal heart disease characterized by fibroadipocytic replacement of cardiac myocytes, accounts for 20% of sudden cardiac death and lacks effective treatment. It is often caused by mutations in desmosome proteins, with Desmoglein-2 (DSG2) mutations as a common etiology. However, the mechanism underlying the accumulation of fibrofatty in ACM remains unknown, which impedes the development of curative treatment. Here we investigated the fat accumulation and the underlying mechanism in a mouse model of ACM induced by cardiac-specific knockout of Dsg2 (CS-Dsg2 -/-). Heart failure and cardiac lipid accumulation were observed in CS-Dsg2 -/- mice. We demonstrated that these phenotypes were caused by decline of fatty acid (FA) β-oxidation resulted from impaired mammalian target of rapamycin (mTOR) signaling. Rapamycin worsened while overexpression of mTOR and 4EBP1 rescued the FA β-oxidation pathway in CS-Dsg2 -/- mice. Reactivation of PPARα by fenofibrate or AAV9-Pparα significantly alleviated the lipid accumulation and restored cardiac function. Our results suggest that impaired mTOR-4EBP1-PPARα-dependent FA β-oxidation contributes to myocardial lipid accumulation in ACM and PPARα may be a potential target for curative treatment of ACM.

Advances in research on the function and disease of desmoglein 2 / 医学研究生学报

Desmoglein (DSG) is an important constituent of desmosome, a single transmembrane glycoprotein that binds to desmocollin (DSC), regulates intercellular adhesion and transmits intracellular and extracelluar signals. Studies have shown that DSG2, one subtype of the DSG, is abnormally expressed in tumor cells and has certain value for targeted treatment and prognosis. This paper reviews the structure, biological functions and related diseases of DSG2 protein.

Immunohistochemical Study on the Expression of Desmocollin 1 during Skin Development / 대한피부과학회지

BACKGROUND: Desmocollins (Dsc) are calcium-dependent transmembrane glycoproteins of desmosomes that are important in the junction complex of epidermis and maintain structural integrity of the skin from external stressors. Among three Dscs (Dsc 1, 2, 3), Dsc 1 and 3 are distributed on skin. OBJECTIVE: The purpose of this study was to observe the Dsc 1 distribution pattern on the skin and oral mucosa during fetal development. METHODS: Skin was obtained from the sole and scalp of 33 fetuses, ranging from 10 to 37 weeks of gestational age. Immunohistochemical staining was performed on the paraffin-embedded tissue using a Dsc 1 monoclonal antibody. RESULTS: Dsc 1 was expressed in the suprabasal layer but not in the basal layer of the epidermis of the sole at the 10th week of gestation. Thereafter, Dsc 1 expression further increased in the suprabasal layer with initiation of stratification and increased gradually in the granular layers of the sole and scalp epidermis. Dsc 1 was strongly expressed in the superficial layer of the infundibulum and inner root sheath of the hair follicle but was not expressed in the sebaceous cells or other hair components. The eccrine duct epithelium was focally and weakly positive for Dsc 1 expression. Furthermore, Dsc 1 was not expressed in oral mucosa, although the oro-cutaneous portion was strongly expressed in the superficial layer. CONCLUSION: Dsc 1 was strongly expressed in the suprabasal cells of the epidermis during fetal skin development, and expression increased gradually in the granular layer and inner root sheath of the hair follicle. However, Dsc 1 was not expressed in basal cells or in oral mucosa. Dsc 1 may play a role in the maintenance of epithelial integrity as part of desmosomes.

Ectodermal dysplasia-skin fragility syndrome.

Ectodermal dysplasia-skin fragility (EDSF) syndrome is a rare and first described inherited disorder of desmosomes. It occurs due to loss-of-function mutations in PKP1 gene resulting in poorly formed desmosomes and loss of desmosomal and epidermal integrity. We report a case of a 2-year-old Indian male child who presented with palmoplantar hyperkeratosis with fissuring, short, sparse, and easily pluckable scalp hair, nail dystrophy, and multiple erosions over the skin. Skin biopsy showed epidermal hyperplasia with widening of intercellular spaces. His developmental milestones were delayed but intelligence was normal. Echocardiography, X-ray chest, and electrocardiogram were normal. Very few cases of this syndrome have been reported in the literature. We consider this as the first case report from India.

Expression of Desmoglein-1 in Fetal Skin Development / 대한피부과학회지

BACKGROUND: Desmosomes are cell-cell adhesion complexes that provide mechanical integrity to keratinocytes by linking them to keratin intermediate filaments. Desmosomes are composed of two major transmembrane proteins, desmoglein and desmocollin. In humans, four desmoglein isoforms have been identified: Dsg1, Dsg2, Dsg3, and Dsg4. Desmogleins are Ca2+-dependent adhesion molecules and play important parts in the formation and maintenance of desmosomes. Desmoglein-1 is the main skin-associated desmosomal cadherin. It is expressed throughout the epidermis, but most prominently in the differentiated layers. OBJECTIVE: The purpose of this study was to observe the distribution pattern of desmoglein-1 in the skin and oral mucosa during fetal development. METHODS: Skin was obtained from the sole and scalp of 35 fetuses, ranging from 10 to 37 weeks of gestational age. Immunohistochemical staining was performed on paraffin embedded tissue using anti-human monoclonal antibody against desmoglein-1. RESULTS: Expression of desmoglein-1 in the epidermis appeared in the upper layer of the sole, but the basal layer was negative at the 10th gestational age. Thereafter, stratification began with stronger expression in the middle layer than in the basal layer of the sole and scalp epidermis. Expression in the middle spinous layer is stronger in the fetal period than in other layers of the epidermis. Expression in the superficial layer seemed to increase in later stages. Expression of desmoglein-1 in hair was strong in the infundibulum, inner root sheath, sebaceous glandular epithelium, and eccrine duct epithelium. Expression of desmoglein-1 in oral lip mucosa was very weak or negative in the upper half of the mucosal epithelium, though the lower half was strongly positive, while the skin side of the mucosa was similar with the sole skin. CONCLUSION: Desmoglein-1 may play a complementary role in the maintenance of epithelial integrity along with other desmogleins, because desmoglein-1 distribution is slightly different from that of desmoglein-3 in epidermis, hair and mucosa in fetal skin development.

Immunohistochemical Study on the Expression of Desmoglein-3 in Fetal Skin Development / 대한피부과학회지

BACKGROUND: Desmogleins are calcium-dependent transmembrane glycoproteins of the desmosome that form an import component of the junction complexes of epithelial cells. Desmogleins are involved in maintaining the structural integrity of tissues. So far, four different desmogleins (Dsg1, Dsg2, Dsg3 and Dsg4) have been identified. OBJECTIVE: The purpose of this study was to observe the distribution pattern of desmoglein-3 in the fetal skin during development. METHODS: Skin was obtained from the sole, scalp and lip of 34 fetuses that ranged in age from 10 to 39 weeks of gestational age. Immunohistochemical staining was performed on the paraffin embedded tissue using anti-human monoclonal antibody against the desmoglein-3. RESULTS: The expression of desmoglein-3 in the epidermis appeared in the basal layer of the sole at the 10th week of gestation age. Thereafter, a stronger expression was noted in the middle layer of the sole and scalp epidermis. The basal layer had a stronger expression than did the other layers of the epidermis, followed by the middle and superficial layers. A stronger expression of desmoglein-3 in hair was noted in the outer root sheath, the bulge cells and the eccrine duct cells. The expression of desmoglein-3 in the lip mucosa was strong in both the basal and middle layers, while the skin side of the mucosa showed a stronger expression in basal layer. CONCLUSION: These results suggested that desmoglein-3 plays an important role in the development and differentiation of the epidermis and skin adnexa in the fetal stage, and especially in basal and suprabasal layers.

Sarcomatoid Renal Cell Carcinoma; Special Reference to its Distinction from Carcinosarcoma

Sarcomatoid renal cell carcinoma is an uncommon tumor that has to be distinguished from renal carcinosarcoma. We have described three cases of sarcomatoid renal cell carcinoma showing different clinical and light microscopic features. An ultrastructural study of the tumor cells from the sarcomatoid area revealed frequent desmosomal junction, confirming the epithelial nature of the neoplasm. All three cases showed an aggressive clinical course and tended to invade adjacent organs or tissues. We believe that an histological and immunohistochemical examination in conjunction with an electron microscopic examination are necessary to diagnose sarcomatoid renal cell carcinoma.

The Effects of Calcium and Retinoic Acid on Epidermal Desmosomes / 대한피부과학회지

BACKGROUND: Desmosomes are adhesive intercellular junctions that form an important component of the junction complexes of epithelial cells. They provide intercellular links between the intermediate filament cytoskeletons of adjacent cells and are thus involved in maintaining the structural integrity of tissues. OBJECTIVE: Calcium and retinoids are major regulators of epidermal differentiation and their role on keratin proteins are well known. However, their effects on desmosome moleucles are unknown. To address this question we initiated a study of the effects of these epidermal differentiation regulators on desmosomal components, i.e., desmoplakin, desmoglein, and pemphigus antigens. METHODS: We used monoclonal antibodies against desmoplakin(DP) and desmoglein(DG), and sera from patients with pemphigus vulgaris(PV), pemphigus foliaceus(PF) and paraneoplastic pemphigus (PNP) to study the effects of calcium and retinoic acids, which are major regulators of epidermal differentation, on desmosomal protein formation in human cultured deratinocytes. We performed immunofluorescence, immunoblotting and immunoprecipitation study using human keratinocytes cultured in high calcium media with or without retinoic acid and in low calcium media with or without retinoic acid. RESULTS: 1. In low calcium (0.15mM) media, PV antigen and DG were produced in a small amount and it appeared that these desmosomal proteins were located in cytosol. Whereas in high calcium (1.8mM) media, production of these desmosomal proteins was increased not they were assembled at the desmosomal structures located in cell-cell contact margins. 2. PF antigen, which was identical to the DG, were not produced or expressed in cultured keratinocytes even when cultured in high calcium media. 3. PNP antigen and DP were produced in cultured keratinocytes grown in both high low calcium media but their production was increased in high calcium media and only in high calcium media they were assembled at the desmosomal structures. 4. Retinoic acids induced loosening of cell-cell contacts of cultured keratinocytes and decreased the production of desmosomal proteins. CONCLUSION: Our results suggests calcium is a major regulator of the production and assembly of desmosomal proteins including pemphigus antigens, but PF sera and monoclonal antibodies against DG show different antigen binding characteristics. It appears that retinoic acids inhibit production of desmosomal proteins.

Desmosome and intermediate filament assembly during differentiation and stratification of epithelial cells.

In the present investigation the sequential expression and organization of keratin intermediate filament proteins were studied in the developing rat palatal epithelia starting from early gestation period to the adult. The distribution and organization of keratin proteins were correlated with the formation and elaboration of desmosornes during differentiation and stratification of the epithelia.

CYTOLOGICAL IDENTIFICATION OF THE MURINE MTEC1 THYMUS EPITHELIAL CELL LINE / 解剖学报

A murine MTEC_1 thymus epithelial cell line established by us has been characterized. The cells were polyhydral and closely packed each other as epithelial like cells. Using anti-keratin antibody, the keratin were shown in cytoplasm of all cells. Under electronmicroscope, bunches of tonofilaments were clearly shown in the cytoplasm, and desmosomes were seen between neighbouring cells. Using anti-mouse epithelial cell monoclonal antibodies for immunohistochemical study, nearly all of the MTEC_1 cells were MTS33 positive. It suggests that MTEC, cells were derived from the epithelial cells located in medulla. The majority of the MTEC_1 cells have normal mouse diploid chomosome number of 40. These results provide evidence that MTEC, cell line is normal murine thymus epithelial cells.