Dapagliflozin attenuates steatosis in livers of high-fat diet-induced mice and oleic acid-treated L02 cells via regulating AMPK/mTOR pathway

Luo, Jingyi; Sun, Pengbo; Wang, Yangyang; Yang, Chen; Niu, Yaoyun; Ding, Yipei; Xu, Ning; Zhang, Y; Xie, Weidong

doi:10.1016/j.ejphar.2021.174304

Cited by 20 publications

(18 citation statements)

References 55 publications

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“…However, oral administration of CANA in mice increased AMPK phosphorylation in liver, but not affected in muscle [ 27 ], which is in part consistent with our study. Currently, there have been some reports that not only CANA but also other SGLT2 inhibitors increase AMPK phosphorylation [ 48 ]; dapagliflozin increased AMPK phosphorylation in myofibroblasts and in high glucose-treated HK-2 cells [ 49 , 50 ], while empagliflozin increased AMPK phosphorylation in myocardial infarction hearts [ 51 ] and improved hepatic steatosis by increasing AMPK phosphorylation [ 52 ]. Therefore, SGLT2 inhibitors could increase AMPK phosphorylation by different concentrations in various cells or tissues, although not significantly observed in the skeletal muscles from nondiabetic mice in this study.…”

Section: Discussionmentioning

confidence: 99%

Differential effect of canagliflozin, a sodium–glucose cotransporter 2 (SGLT2) inhibitor, on slow and fast skeletal muscles from nondiabetic mice

Otsuka

Yokomizo

Nakamura

et al. 2022

Biochemical Journal

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There has been a concern that sodium-glucose cotransporter 2 (SGLT2) inhibitors could reduce skeletal muscle mass and function. Here, we examine the effect of canagliflozin (CANA), an SGLT2 inhibitor, on slow and fast muscles from nondiabetic C57BL/6J mice. In this study, mice were fed with or without CANA under ad libitum feeding, and then evaluated for metabolic valuables as well as slow and fast muscle mass and function. We also examined the effect of CANA on gene expressions and metabolites in slow and fast muscles. During SGLT2 inhibition, fast muscle function is increased, as accompanied by increased food intake, whereas slow muscle function is unaffected, although slow and fast muscle mass is maintained. When the amount of food in CANA-treated mice is adjusted to that in vehicle-treated mice, fast muscle mass and function are reduced, but slow muscle was unaffected during SGLT2 inhibition. In metabolome analysis, glycolytic metabolites and ATP are increased in fast muscle, whereas glycolytic metabolites are reduced but ATP is maintained in slow muscle during SGLT2 inhibition. Amino acids and free fatty acids are increased in slow muscle, but unchanged in fast muscle during SGLT2 inhibition. The metabolic effects on slow and fast muscles are exaggerated when food intake is restricted. This study demonstrates the differential effects of an SGLT2 inhibitor on slow and fast muscles independent of impaired glucose metabolism, thereby providing new insights into how they should be used in patients with diabetes, who are at a high risk of sarcopenia.

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Section: Discussionmentioning

confidence: 99%

Differential effect of canagliflozin, a sodium–glucose cotransporter 2 (SGLT2) inhibitor, on slow and fast skeletal muscles from nondiabetic mice

Otsuka

Yokomizo

Nakamura

et al. 2022

Biochemical Journal

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“…The expression of both SGLT-1 and SGLT-2 co-transporters has been reported in human hepatocellular carcinoma cells (HepG2) [ 81 , 82 , 83 ], whilst SGLT-2 has also been identified in immortalized human primary hepatocyte cells (HuS-E/2), as well as immortalized normal human hepatocyte-derived liver cells (L02) [ 84 , 85 ].…”

Section: Sglt-2 Inhibitors In Nafldmentioning

confidence: 99%

“…Dapagliflozin treatment remarkably suppressed oleic acid (OA)-induced lipid accumulation and TG content in L02 cells through increased FA β-oxidation, as indicated by elevated proliferator-activated receptor-gamma coactivator-1 alpha (PGC-1α) levels and activation of the AMP-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR) signaling pathway [ 84 ]. Several in vitro studies have shown that AMPK is a key regulator that mediates the various beneficial effects of SGLT-2i related to cholesterol and glucose metabolism in hepatic cells.…”

Section: Sglt-2 Inhibitors In Nafldmentioning

confidence: 99%

“…AMPK activation by dapagliflozin prevented glucose absorption through reduced SGLT-2 expression in OA-stimulated HuS-E/2 cells [ 90 ]. This effect was eliminated after incubation of cells with compound C, a potent AMPK inhibitor [ 84 ]. Moreover, treatment of HepG2 cells with canagliflozin facilitated hepatic cholesterol efflux via activation of AMPK.…”

Section: Sglt-2 Inhibitors In Nafldmentioning

confidence: 99%

“…It is known that SGLT-2i reduces cellular ATP levels and indirectly activates the AMPK signaling pathway [ 83 , 93 ]. It has been shown that dapagliflozin alleviates the intracellular ATP levels via regulation of glucose metabolism [ 84 ].…”

Section: Sglt-2 Inhibitors In Nafldmentioning

confidence: 99%

See 2 more Smart Citations

SGLT-2 Inhibitors in NAFLD: Expanding Their Role beyond Diabetes and Cardioprotection

Ανδρουτσάκος

Nasiri-Ansari

Bakasis

et al. 2022

IJMS

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Non-alcoholic fatty liver disease (NAFLD) is an ‘umbrella’ term, comprising a spectrum ranging from benign, liver steatosis to non-alcoholic steatohepatitis, liver fibrosis and eventually cirrhosis and hepatocellular carcinoma. NAFLD has evolved as a major health problem in recent years. Discovering ways to prevent or delay the progression of NAFLD has become a global focus. Lifestyle modifications remain the cornerstone of NAFLD treatment, even though various pharmaceutical interventions are currently under clinical trial. Among them, sodium-glucose co-transporter type-2 inhibitors (SGLT-2i) are emerging as promising agents. Processes regulated by SGLT-2i, such as endoplasmic reticulum (ER) and oxidative stress, low-grade inflammation, autophagy and apoptosis are all implicated in NAFLD pathogenesis. In this review, we summarize the current understanding of the NAFLD pathophysiology, and specifically focus on the potential impact of SGLT-2i in NAFLD development and progression, providing current evidence from in vitro, animal and human studies. Given this evidence, further mechanistic studies would advance our understanding of the exact mechanisms underlying the pathogenesis of NAFLD and the potential beneficial actions of SGLT-2i in the context of NAFLD treatment.

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Dapagliflozin as an autophagic enhancer via LKB1/AMPK/SIRT1 pathway in ovariectomized/d-galactose Alzheimer’s rat model

et al. 2022

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Autophagy and mitochondrial deficits are characteristics of early phase of Alzheimer’s disease (AD). Sodium-glucose cotransporter-2 inhibitors have been nominated as a promising class against AD hallmarks. However, there are no available data yet to discuss the impact of gliflozins on autophagic pathways in AD. Peripherally, dapagliflozin’s (DAPA) effect is mostly owed to autophagic signals. Thus, the goal of this study is to screen the power of DAPA centrally on LKB1/AMPK/SIRT1/mTOR signaling in the ovariectomized/d-galactose (OVX/d-Gal) rat model. Animals were arbitrarily distributed between 5 groups; the first group undergone sham operation, while remaining groups undergone OVX followed by d-Gal (150 mg/kg/day; i.p.) for 70 days. After 6 weeks, the third, fourth, and fifth groups received DAPA (1 mg/kg/day; p.o.); concomitantly with the AMPK inhibitor dorsomorphin (DORSO, 25 µg/rat, i.v.) in the fourth group and the SIRT1 inhibitor EX-527 (10 µg/rat, i.v.) in the fifth group. DAPA mitigated cognitive deficits of OVX/d-Gal rats, as mirrored in neurobehavioral task with hippocampal histopathological examination and immunohistochemical aggregates of p-Tau. The neuroprotective effect of DAPA was manifested by elevation of energy sensors; AMP/ATP ratio and LKB1/AMPK protein expressions along with autophagic markers; SIRT1, Beclin1, and LC3B expressions. Downstream the latter, DAPA boosted mTOR and mitochondrial function; TFAM, in contrary lessened BACE1. Herein, DORSO or EX-527 co-administration prohibited DAPA’s actions where DORSO elucidated DAPA’s direct effect on LKB1 while EX-527 mirrored its indirect effect on SIRT1. Therefore, DAPA implied its anti-AD effect, at least in part, via boosting hippocampal LKB1/AMPK/SIRT1/mTOR signaling in OVX/d-Gal rat model. Graphical abstract

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Dapagliflozin attenuates steatosis in livers of high-fat diet-induced mice and oleic acid-treated L02 cells via regulating AMPK/mTOR pathway

Cited by 20 publications

References 55 publications

Differential effect of canagliflozin, a sodium–glucose cotransporter 2 (SGLT2) inhibitor, on slow and fast skeletal muscles from nondiabetic mice

Differential effect of canagliflozin, a sodium–glucose cotransporter 2 (SGLT2) inhibitor, on slow and fast skeletal muscles from nondiabetic mice

SGLT-2 Inhibitors in NAFLD: Expanding Their Role beyond Diabetes and Cardioprotection

Dapagliflozin as an autophagic enhancer via LKB1/AMPK/SIRT1 pathway in ovariectomized/d-galactose Alzheimer’s rat model

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