Abstract
Background: The gender disparity in lipid metabolism leaves more women with uncontrolled hyperlipidemia by current medication. Thus, discovering female-preferred anti-hyperlipidemic drugs is favorable to large numbers of women patients. Methods: We investigated the ameliorating effects of 1-deoxynojirimycin (DNJ) on hyperlipidemia and hyperglycemia in both male and female mice received high-fat diet (HFD) feeding and a single small dose of streptozocin (30 mg/kg, i.p. ). The gut microbial composition was analyzed by both 16S rDNA and 16S rRNA pyrosequencing. The metabonomic analysis on feces was performed by gas chromatography–time-of-flight mass spectrometry (GC–TOF/MS). The lipid-lowering effect of indole-3-propionic acid (IPA) was evaluated in vitro and in vivo. Findings: DNJ female-preferably alleviated hyperlipidemia but homogenously diminished hyperglycemia in diabetic mice. Oral administration of DNJ gender-specifically downregulated the expression of lipogenic genes, stimulated the growth of Akkermansia and Clostridium XIVa, and promoted the generation of indole-3-propionic acid (IPA) which tightly associated with the anti-hyperlipidemic effect of DNJ and exhibited a potent lipid-lowering effect in HepG2 cells and high-fat diet-induced obese mice. Interpretation: Our results propose DNJ as a female-preferable anti-hyperlipidemic candidate via gender-specifically modulation of gut microbial community and their metabolites, which provides insights for discovering novel gender-specific medications against hyperlipidemia. Funding Statement: This work was supported financially by the National Natural Science Foundation of China (81403155), Modern Agro-industry Technology Research System of China (CARS-18) and Key Laboratory of Creative Agriculture, Ministry of Agriculture, P.R. China Declaration of Interests: The authors declare that they have no competing interests. Ethics Approval Statement: All the animal experiments were performed following the National Institutes of Health guide for the care and use of Laboratory Animals (NIH Publications No. 8023, revised 1978) and were approved by the Medical Ethics Committee of Zhejiang Academy of Agricultural Sciences (No. ZAAS-20170812011).
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