Abstract
Bioassay-guided fractionation of marine-derived fungi revealed that the EtOAc fraction from the fermentation broth of a mutated fungal strain Streptomyces nitrosporeus YBH10-5 had lipid-lowering effects in HepG2 cells. Chromatographic separation of the EtOAc fraction resulted in the isolation of 11 PKS-based derivatives, including a structurally unique meroterpenoid namely nitrosporeunol H (1). The structure of compound 1 was determined by the analysis of spectroscopic data. Further bioassay resulted in farnesylquinone (2) and its analogues to exert in vivo fat-reducing effects in C. elegans worm model. The underlying mode of action of compound 2 in the context of live worms was investigated, uncovering that compound 2 enhanced the mitochondrial β-oxidation rate and changed the transcriptional level of energy metabolism genes. Additional experiments revealed that compound 2 exerted its effects in C. elegans partially through repressing FAT-5, an isoform of stearoyl-CoA desaturase (SCD) which catalyzes the conversion of saturated fatty acids to monounsaturated fatty acids, thereafter leading to the modification of the fatty acid profile. Thus, compound 2 was suggested to be a promising lead for further optimization to treat obesity.
Highlights
Metabolic diseases, such as diabetes, obesity, and atherosclerosis caused serious problems in global human health [1]
The results showed that compound 2 obviously alleviated steatosis in HepG2 cells (Figure 5D), indicating that the action of compound 2 on C. elegans is relevant to the mammalian system
Since lipid content modulation is a physiologically relevant phenotype that is the outcome of an array of integrated pathways, it is likely that compound 2 works on an additional set of targets or effector proteins; impaired FAT-5 probably leads to a knock-on effect in an intricate feedback and compensation energy system
Summary
Metabolic diseases, such as diabetes, obesity, and atherosclerosis caused serious problems in global human health [1]. Obesity is a related metabolic disorder that has been a serious threat to human health worldwide with an increased incidence of metabolic diseases [2]. It is caused by an excess of adipose tissue and an imbalance between energy intake and expenditure and is attributed to the diet, genetic disorders, sedentary lifestyle, and psychological factors, that increases the risk of developing type 2 diabetes, hypertension, and cardiovascular diseases [3]. Natural products provided as a promising source for the discovery of lead compounds to combat obesity and its related diseases.
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
