Propionate alleviates high-fat diet-induced lipid dysmetabolism by modulating gut microbiota in mice.

AIMS: The aims were to examine whether oral sodium propionate supplementation regulate lipid metabolism through modulating gut microbiota. METHODS AND RESULTS: ICR male mice (26·98 ± 0·30 g) were randomly assigned to three groups (n = 10) and fed control diet (Con), high-fat diet (HFD) and HFD plus propionate (Pro) respectively. In this study, we found that HFD increased the weight of final body, inguinal white adipose tissues (iWAT), epididymal white adipose tissue (eWAT) and perirenal white adipose tissue (pWAT), as well as the adipocyte mean area of iWAT and eWAT in mice (P < 0·05), whereas sodium propionate treatment reduced the weight of iWAT and pWAT as well as adipocyte mean area of iWAT in mice fed a HFD (P < 0·05). Moreover, in the iWAT, the mRNA expression of lipogenesis genes, including peroxisome proliferator activated receptor γ, acetyl-CoA carboxylase and carnitine palmitoyl transferase-1ß, was upregulated by HFD challenge (P < 0·05), and the elevation of these genes was nearly reversed to the level of control diet-fed mice by sodium propionate treatment. Meanwhile, sodium propionate treatment increased the hormone-sensitive lipase mRNA expression in the iWAT of HFD-fed mice (P < 0·05). High-throughput pyrosequencing of the 16S rRNA demonstrated that sodium propionate treatment significantly recovered the gut microbiota dysbiosis in HFD-fed mice, including the richness and diversity of microbiota and the ratio of Firmicutes to Bacteroidetes. Furthermore, the HFD-induced reductions in colonic levels of butyrate and valerate were reversed by sodium propionate treatment, which also normalized the serum LPS level seen in HFD-fed mice to the levels of the control diet-fed mice. CONCLUSIONS: Collectively, these results indicated that sodium propionate treatment could improve lipid metabolism in HFD-fed mice, and the potential mechanisms might be via regulating gut microbiota. SIGNIFICANCE AND IMPACT OF THE STUDY: We demonstrated for the first time that oral sodium propionate significantly improved HFD-induced dysbiosis of gut microbiota, indicating that the mitigative effect of propionate for HFD-induced lipid dysmetabolism might be mediated by gut microbiota in mice.

Inhibition of reduced glutathione synthesis by cyanobacterial alkaloid cylindrospermopsin in cultured rat hepatocytes.

Cylindrospermopsin (CY) is a naturally occurring alkaloid produced by the cyanobacterium Cylindrospermopsis raciborskii, which has been linked to an outbreak of hepatoenteritis in humans. We previously showed that CY is cytotoxic to primary cultures of rat hepatocytes and that CY lowers cell reduced glutathione (GSH) at nontoxic doses. Lower cell GSH also potentiates CY-induced cytotoxicity (Runnegar et al., Biochem Biophys Res Commun 201: 235-241, 1994). Our current work examined the mechanism of the fall in cell GSH induced by CY. We excluded several possible explanations for the loss in GSH, namely increased formation of oxidized glutathione (GSSG), increased GSH efflux, hidden forms of GSH, decreased GSH precursor availability, or decreased cellular ATP level. To address whether the fall in GSH was due to decreased GSH synthesis or increased GSH consumption, we examined the rate of fall in total GSH after 5 mM buthionine sulfoximine (BSO, an irreversible inhibitor of GSH synthesis) treatment. The rates of fall in total GSH (nmol/10(6) cells/hr) were 8.2 +/- 2.5, 6.0 +/- 1.7 and 5.9 +/- 1.3 for control, 2.5 microM and 5 microM CY-pretreated cells, respectively. This suggests that the fall in GSH induced by CY was due to the inhibition of GSH synthesis rather than increased consumption, because in the latter case the rate of fall in GSH would have been accelerated by CY pretreatment. Furthermore, excess GSH precursor (20 mM N-acetylcysteine), which supported GSH synthesis in control cells, did not prevent the fall in GSH or toxicity induced by CY. Treatment of cells with the cytochrome P450 inhibitor alpha-naphthoflavone protected partially from CY-mediated toxicity and from the fall in cell GSH. Thus, it is likely that cytochrome P450 is involved in the metabolism of CY, and the metabolite(s) that is generated may be more toxic and/or potent in inhibiting GSH synthesis. Inhibition of GSH synthesis is most likely an important factor in the cytotoxicity of CY.

The role of glutathione in the toxicity of a novel cyanobacterial alkaloid cylindrospermopsin in cultured rat hepatocytes.

Cylindrospermopsin (CY) is a newly isolated alkaloid produced by the cyanobacterium Cylindrospermopsis raciborskii, which has been linked to an outbreak of hepatoenteritis in man. The current work examined the suitability of primary cultures of rat hepatocytes as an in vitro model for studying the cytotoxicity of CY. We found that CY (3.3-5.0 microM) caused significant cell death (40-67% of cells by LDH release) in cultured hepatocytes after 18 hr incubation. While investigating possible mechanisms for CY toxicity, we found that lower, nontoxic doses of CY (1.6-2.5 microM) decreased cell glutathione (GSH) to about 50% of control. For toxic doses (5 microM), the loss of GSH preceded the onset of toxicity by six hr. Lowering cell GSH predisposed cells to CY toxicity. In conclusion, cultured hepatocytes are a suitable model for studies of CY cytotoxicity and GSH is involved in the detoxification of CY.