As a newly approved oral hypoglycaemic agent, the sodium-glucose cotransporter 2 (SGLT2) inhibitor dapagliflozin, which is derived from the natural product phlorizin can effectively reduce blood glucose. Recent clinical studies have found that dapagliflozin alleviates non-alcoholic fatty liver disease (NAFLD), but the specific mechanism remains to be explored. This study aimed to investigate the underlying mechanism of dapagliflozin in alleviating hepatocyte steatosis in vitro and in vivo. We fed the spontaneous type 2 diabetes mellitus rats with high-fat diets and cultured human normal liver LO2 cells and human hepatocellular carcinoma HepG2 cells with palmitic acid (PA) to induce hepatocellular steatosis. Dapagliflozin attenuated hepatic lipid accumulation both in vitro and in vivo. In Zucker diabetic fatty (ZDF) rats, dapagliflozin reduced hepatic lipid accumulation via promoting phosphorylation of acetyl-CoA carboxylase 1 (ACC1), and upregulating lipid β-oxidation enzyme acyl-CoA oxidase 1 (ACOX1). Furthermore, dapagliflozin increased the expression of the autophagy-related markers LC3B and Beclin1, in parallel with a drop in p62 level. Similar effects were observed in PA-stimulated LO2 cells and HepG2 cells. Dapagliflozin treatment could also significantly activated AMPK and reduced the phosphorylation of mTOR in ZDF rats and PA-stimulated LO2 cells and HepG2 cells. We demonstrated that dapagliflozin ameliorates hepatic steatosis by decreasing lipogenic enzyme, while inducing fatty acid oxidation enzyme and autophagy, which could be associated with AMPK activation. Moreover, our results indicate that dapagliflozin induces autophagy via the AMPK-mTOR pathway. These findings reveal a novel clinical application and functional mechanism of dapagliflozin in the treatment of NAFLD.
Osteoporosis is a global health issue among the aging population. The effect of the acid or base interventions on bone health remains controversial. This study performed a systematic review and meta-analysis to investigate effects of acidic diets and alkaline supplements on bone health simultaneously. We conducted a comprehensive literature search in 5 available databases and 1 registered clinical trial system to identify randomized controlled trials (RCTs) that assessed effects of the acid-base intervention on bone health. Depending on heterogeneity across studies, the pooled effects were calculated by fixed-effects or random-effects models. The present study included 13 acidic diet intervention studies and 13 alkaline supplement studies for final quantitative assessments. The meta-analysis showed that acidic diets significantly increased net acid excretion [NAE; standardized mean difference (SMD) = 2.99; P = 0.003] and urinary calcium excretion (SMD = 0.47, P < 0.00001) but had no significant effect on bone turnover markers and bone mineral density (BMD). On the other hand, alkaline supplement intervention significantly reduced NAE (SMD = −1.29, P < 0.00001), urinary calcium excretion (SMD = −0.44, P = 0.007), bone resorption marker aminoterminal cross-linking telopeptide (NTX; SMD = −0.29, P = 0.003), and bone formation marker osteocalcin (OC; SMD = −0.23, P = 0.02), but did not affect the other bone turnover markers. Furthermore, alkaline supplements significantly increased BMD in femoral neck [mean difference (MD) = 1.62, P < 0.00001, I2 = 0%], lumbar spine (MD = 1.66, P < 0.00001, I2 = 87%), and total hip (MD = 0.98, P = 0.02, I2 = 99%). Subsequently, meta-regression analyses identified 1 study that substantially contributed to the high heterogeneity of BMD in the latter 2 sites, but sensitivity analysis suggested that this study did not affect the significant pooled effects. Despite that, the results should be interpreted with caution and need to be further validated by a larger RCT. In summary, through integrating evidence from RCTs, the present meta-analysis initially suggests that alkaline supplements may be beneficial to bone metabolism and acidic diets may not be harmful to bone health. This work may be clinically useful for both clinicians and patients with osteoporosis.
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