Empagliflozin activates Sestrin2-mediated AMPK/mTOR pathway and ameliorates lipid accumulation in obesity-related nonalcoholic fatty liver disease

Abstract

Empagliflozin (EMPA) therapy has led to improvements in patients with non-alcoholic fatty liver disease (NAFLD). Sestrin2 is a stress-inducible protein that controls the AMPK-mTOR pathway and inhibits oxidative damage in cells. This study investigated the functional implications of EMPA on the multifactorial pathogenesis of NAFLD and potential underlying molecular mechanisms of pathogenesis. An in vitro model of NAFLD was established by treating HepG2 cells with palmitic acid (PA); an in vivo model of NAFLD was generated by feeding C57BL/6 mice a high-fat diet. Investigations of morphology and lipid deposition in liver tissue were performed. Expression patterns of Sestrin2 and genes related to lipogenesis and inflammation were assessed by reverse transcription polymerase chain reaction. Protein levels of Sestrin2 and AMPK/mTOR pathway components were detected by Western blotting. NAFLD liver tissues and PA-stimulated HepG2 cells exhibited excessive lipid production and triglyceride secretion, along with upregulation of Sestrin2 and increased expression of lipogenesis-related genes. EMPA treatment reversed liver damage by upregulating Sestrin2 and activating the AMPK-mTOR pathway. Knockdown of Sestrin2 effectively increased lipogenesis and enhanced the mRNA expression levels of lipogenic and pro-inflammatory genes in PA-stimulated HepG2 cells; EMPA treatment did not affect these changes. Furthermore, Sestrin2 knockdown inhibited AMPK-mTOR signaling pathway activity. The upregulation of Sestrin2 after treatment with EMPA protects against lipid deposition-related metabolic disorders; it also inhibits lipogenesis and inflammation through activation of the AMPK-mTOR signaling pathway. These results suggest that Sestrin2 can be targeted by EMPA therapy to alleviate lipogenesis and inflammation in obesity-related NAFLD.

Xanthohumol alleviates palmitate-induced inflammation and prevents osteoarthritis progression by attenuating mitochondria dysfunction/NLRP3 inflammasome axis

“…Such as, PA-treated HK-2 renal tubular cells were used for in vitro assessments of obesity-induced nephropathy [ 39 ]. The in vitro model of non-alcoholic fatty liver disease was established by treating HepG2 cells with PA [ 40 ]. Moreover, PA-induced osteoarthritis cell models was well used to study obesity-related OA [ 41 , 42 ], hence, we used PA treated chondrocyte cell model for further studies.…”

Empagliflozin Reverses Oxidized LDL-Induced RECK Suppression, Cardiotrophin-1 Expression, MMP Activation, and Human Aortic Smooth Muscle Cell Proliferation and Migration

“…While empagliflozin's primary mechanism of action is through the inhibition of SGLT2 in the kidney, it has also been shown to affect intracellular signaling pathways in various cell types. For instance, empagliflozin has been reported to activate adenosine monophosphate-activated protein kinase (AMPK) in the liver ameliorating lipid accumulation in obesity-related nonalcoholic fatty liver disease [ 54 ] and in skeletal muscle promoting fat utilization and hence presumably contributing to improved insulin sensitivity [ 55 , 56 ]. Additionally, empagliflozin-activation of AMPK in cardiomyocytes has been shown to reduce lipopolysaccharide (LPS)-induced inflammatory response and counteract LPS-impaired cellular ATP/ADP ratio, suggesting potential mechanisms for cardioprotection.…”

Recent Insights into the Biomarkers, Molecular Targets and Mechanisms of Non-Alcoholic Steatohepatitis-Driven Hepatocarcinogenesis

“…Among proteins involved in the development of liver tissue cellular defense against oxidative stress, oxidative DNA damage, inflammation, and steatohepatitis, peroxiredoxins 1 (Prx1) and 6 (Prdx6) and sestrin 2 (SESN2) were considered promising potential diagnostic biomarkers for the early stage of NAFLD/NASH, which may also influence the mTOR [ 27 , 28 ] ( Table 1 and Table 2 ). Prdx1 and Prdx6 are involved in Akt/mTOR, AMPK/mTOR, PI3K/Akt, FoxO and p53 signaling pathways, and ubiquitin-mediated proteolysis [ 59 , 60 ].…”

“…Prdx1 and Prdx6 are involved in Akt/mTOR, AMPK/mTOR, PI3K/Akt, FoxO and p53 signaling pathways, and ubiquitin-mediated proteolysis [ 59 , 60 ]. It was also demonstrated that protein levels of SESN2 were positively correlated with AMPK/mTOR pathway components and induced expression of lipogenesis-related genes in NAFLD model HFD-fed C57BL/6 mice liver and palmitic acid (PA)-stimulated HepG2 cells [ 28 ].…”