Sphingomyelin synthase 2 (SMS2) is the synthetic enzyme of sphingomyelin (SM), which regulates membrane fluidity and microdomain structure. SMS2 plays a role in LPS-induced lung injury and inflammation; however, its role in inflammation-mediated tumorigenesis is unclear. We investigated the effect of SMS2 deficiency on dextran sodium sulfate (DSS)-induced murine colitis and found inhibition of DSS-induced inflammation in SMS2-deficient (SMS2 2/2 ) mice. DSS treatment induced a significant increase in ceramide levels, with a decrease of SM levels in SMS2 2/2 colon tissue, and demonstrated attenuation of the elevation of both inflammation-related gene expression and proinflammatory cytokines and chemokines, leukocyte infiltration, and MAPK and signal transducer and activator of transcription 3 activation. After undergoing transplantation of wild-type bone marrow, SMS2 2/2 mice also exhibited inhibition of DSS-induced inflammation in the colon, which suggested that SMS2 deficiency in bone marrow-derived immune cells was not involved in the inhibition of colitis. Finally, in an azoxymethane/DSS-induced cancer model, SMS2 deficiency significantly decreased tumor incidence in the colon. Our results demonstrate that SMS2 deficiency inhibits DSS-induced colitis and subsequent colitis-associated colon cancer via inhibition of colon epithelial cell-mediated inflammation; therefore, inhibition of SMS2 may be a potential therapeutic target for human colitis and colorectal cancer.-Ohnishi, T., Hashizume, C., Taniguchi, M., Furumoto, H., Han, J., Gao, R., Kinami, S., Kosaka, T., Okazaki, T. Sphingomyelin synthase 2 deficiency inhibits the induction of murine colitis-associated colon cancer. FASEB J. 31, 3816-3830 (2017). www.fasebj.orgIn the past decade, a positive correlation between inflammation and tumorigenesis has been identified, with supporting evidence from genetic, pharmacologic, and epidemiologic data in numerous organs, including colon, lungs, bladder, and ovaries (1, 2). Colorectal cancer (CRC) is one of the most common cancers worldwide. More than 1 million new cases of CRC are reported annually and the incidence rate has been increasing (3). Although most cases of CRC are sporadic, more than 20% of patients with inflammatory bowel disease (IBD), including ulcerative colitis and Crohn's disease, develop colitis-associated colon cancer (CAC) (4). Thus, IBD is recognized as an important risk factor for the development of CRC. Experimental evidence suggests that inflammatory changes create a favorable microenvironment for initiation of CAC and tumor progression (5); however, the pathogenic mechanism that links IBD and CAC is not fully understood.It has been reported that dysregulation of lipid metabolism is a crucial factor in cancer initiation and contributes to the development of CRC (6). Among lipids, sphingolipids, including sphingomyelin (SM), ceramide, and sphingosine-1-phosphate (S1P), are a class of lipids that share sphingoid base as a structural backbone. Sphingolipids have been known as structur...

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Dietary polyunsaturated fatty acids (PUFA), especially eicosapentaenoic acid (EPA), improve lipid metabolism and contribute to the prevention of vascular diseases such as atherosclerosis. However, EPA in the diet is easily oxidized at room temperature and several types of oxidized EPA (OEPA) derivatives are generated. To compare the efficiencies of OEPAs on lipid metabolism with EPA, human hepatocellular liver carcinoma cell line (HepG2) was treated with EPA or OEPAs and their effects on lipid metabolism related genes were studied. OEPAs more potently suppressed the expression of sterol-responsive element-binding protein (SREBP)-1c, a major transcription factor that activates the expression of lipogenic genes, and its downstream target genes than did EPA under conditions of lipid synthesis enhanced by T0901317, a synthetic liver X receptor (LXR) agonist. Furthermore, PGC-1β, a coactivator of both LXRα and SREBP-1, was markedly down-regulated by OEPAs compared with EPA. The treatment of OEPAs also significantly down-regulated the expression of glycerol-3-phosphate acyltransferase (GPA), the initiating enzyme in triacylglycerol (TG) synthesis, more than EPA. Therefore, the advantageous effects of OEPAs on cardiovascular diseases might be due to their SREBP-1c, PGC-1β and GPA mediated ameliorating effects.

Hydroxy and oxo fatty acids were recently found to be produced as intermediates during gut microbial fatty acid metabolism. Lactobacillus plantarum produces these fatty acids from unsaturated fatty acids such as linoleic acid. In this study, we investigated the effects of these gut microbial fatty acid metabolites on the lipogenesis in liver cells. We screened their effect on sterol regulatory element binding protein-1c (SREBP-1c) expression in HepG2 cells treated with a synthetic liver X receptor α (LXRα) agonist (T0901317). The results showed that 10-hydroxy-12(Z)-octadecenoic acid (18:1) (HYA), 10-hydroxy-6(Z),12(Z)-octadecadienoic acid (18:2) (γHYA), 10-oxo-12(Z)-18:1 (KetoA), and 10-oxo-6(Z),12(Z)-18:2 (γKetoA) significantly decreased SREBP-1c mRNA expression induced by T0901317. These fatty acids also downregulated the mRNA expression of lipogenic genes by suppressing LXRα activity and inhibiting SREBP-1 maturation. Oral administration of KetoA, which effectively reduced triacylglycerol accumulation and acetyl-CoA carboxylase 2 (ACC2) expression in HepG2 cells, for 2 weeks significantly decreased Srebp-1c, Scd-1, and Acc2 expression in the liver of mice fed a high-sucrose diet. Our findings suggest that the hypolipidemic effect of the fatty acid metabolites produced by L. plantarum can be exploited in the treatment of cardiovascular diseases or dyslipidemia.

Objectives Hair loss, including alopecia, is a common dermatological issue worldwide. At present, the application of fractional carbon dioxide (CO2) laser in the treatment of alopecia has been documented; however, the results vary between reports. These varying results may be due to the limited knowledge of cellular action in laser‐irradiated skin. The objective of this study was to investigate the molecular and cellular mechanisms of laser treatment under effective conditions for hair cycle initiation. Methods A fractional CO2 laser was applied and optimized to initiate the hair cycle in a mouse model of alopecia. Several cellular markers were analyzed in the irradiated skin using immunofluorescence staining. Cellular populations and their comprehensive gene expression were analyzed using single‐cell RNA sequencing and bioinformatics. Results The effective irradiation condition for initiating the hair cycle was found to be 15 mJ energy/spot, which generates approximately 500 μm depth columns, but does not penetrate the dermis, only reaching approximately 1 spot/mm2. The proportion of macrophage clusters significantly increased upon irradiation, whereas the proportion of fibroblast clusters decreased. The macrophages strongly expressed C–C chemokine receptor type 2 (Ccr2), which is known to be a key signal for injury‐induced hair growth. Conclusions We found that fractional CO2 laser irradiation recruited Ccr2 positive macrophages, and induced hair regrowth in a mouse alopecia model. These findings may contribute to the development of stable and effective fractional laser irradiation conditions for human alopecia treatment.