MCAD activation by empagliflozin promotes fatty acid oxidation and reduces lipid deposition in NASH

Wang, Yi; Shen, Qi Ling; Qi, Xin; Sun, Bei; Shi, Z.; Fang, Qianhua; Shi, Yimin; Niu, Wenyan; Lin, Jingna; Li, Chunjun

doi:10.1530/jme-22-0022

Cited by 4 publications

(2 citation statements)

References 26 publications

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“…The previous study found that the MCAD levels in the liver were significantly reduced in NASH patients compared to patients without NASH. Moreover, upregulation of MCAD expression also reduced lipid deposition and improved NASH in vivo and in vitro ( 20 ). Therefore, based on the above results, it is concluded that hepatic fat accumulation in Wnt+ HFD-fed mice may be due to increased lipid synthesis and decreased oxidative catabolism caused by Wnt/β-catenin signaling activation.…”

Section: Discussionmentioning

confidence: 99%

Wnt/β-catenin signaling activation promotes lipogenesis in the steatotic liver via physical mTOR interaction

Wang,

Zhang,

Lehwald

et al. 2023

Front. Endocrinol.

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Background and aimsWnt/β-catenin signaling plays an important role in regulating hepatic metabolism. This study is to explore the molecular mechanisms underlying the potential crosstalk between Wnt/β-catenin and mTOR signaling in hepatic steatosis.MethodsTransgenic mice (overexpress Wnt1 in hepatocytes, Wnt+) mice and wild-type littermates were given high fat diet (HFD) for 12 weeks to induce hepatic steatosis. Mouse hepatocytes cells (AML12) and those transfected to cause constitutive β-catenin stabilization (S33Y) were treated with oleic acid for lipid accumulation.ResultsWnt+ mice developed more hepatic steatosis in response to HFD. Immunoblot shows a significant increase in the expression of fatty acid synthesis-related genes (SREBP-1 and its downstream targets ACC, AceCS1, and FASN) and a decrease in fatty acid oxidation gene (MCAD) in Wnt+ mice livers under HFD. Wnt+ mice also revealed increased Akt signaling and its downstream target gene mTOR in response to HFD. In vitro, increased lipid accumulation was detected in S33Y cells in response to oleic acid compared to AML12 cells reinforcing the in vivo findings. mTOR inhibition by rapamycin led to a down-regulation of fatty acid synthesis in S33Y cells. In addition, β-catenin has a physical interaction with mTOR as verified by co-immunoprecipitation in hepatocytes.ConclusionsTaken together, our results demonstrate that β-catenin stabilization through Wnt signaling serves a central role in lipid metabolism in the steatotic liver through up-regulation of fatty acid synthesis via Akt/mTOR signaling. These findings suggest hepatic Wnt signaling may represent a therapeutic strategy in hepatic steatosis.

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Section: Discussionmentioning

confidence: 99%

Wnt/β-catenin signaling activation promotes lipogenesis in the steatotic liver via physical mTOR interaction

Wang,

Zhang,

Lehwald

et al. 2023

Front. Endocrinol.

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“…In the current study, we found that CPT1α was decreased in NAFLD mice and OA-induced cells, which was the same as in a previous study ( Pan et al, 2021 ). Moreover, Wang and colleagues indicates that the activation of the AMPK/Foxa2 pathway can upregulate the expression of medium-chain acyl-CoA dehydrogenase, thereby promoting fatty acid oxidation and reducing lipid accumulation in nonalcoholic steatohepatitis ( Wang et al, 2022 ). In our study, overexpression of Foxa2 reversed the upregulation of FAS and ACC and the downregulation of CPT1α in NAFLD mice and OA-stimulated HepG2 cells.…”

Section: Discussionmentioning

confidence: 99%

Foxa2 attenuates steatosis and inhibits the NF-κB/IKK signaling pathway in nonalcoholic fatty liver disease

Yang,

Ma,

Chen

et al. 2023

PeerJ

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Objective Forkhead box a2 (Foxa2) is proven to be an insulin-sensitive transcriptional regulator and affects hepatic steatosis. This study aims to investigate the mechanism by which Foxa2 affects nonalcoholic fatty liver disease (NAFLD). Methods Animal and cellular models of NAFLD were constructed using high-fat diet (HFD) feeding and oleic acid (OA) stimulation, respectively. NAFLD mice received tail vein injections of either an overexpressing negative control (oe-NC) or Foxa2 (oe-Foxa2) for four weeks. HepG2 cells were transfected with oe-NC and oe-Foxa2 for 48 h before OA stimulation. Histological changes and lipid accumulation were assessed using hematoxylin-eosin staining and oil red O staining, respectively. Expression of Foxa2, NF-κB/IKK pathway proteins, lipid synthesis proteins, and fatty acid β-oxidation protein in HFD mice and OA-induced HepG2 cells was detected using western blot. Results Foxa2 expression was downregulated in HFD mice and OA-induced HepG2 cells. Foxa2 overexpression attenuated lipid accumulation and liver injury, and reduced the levels of aspartate aminotransferase, alanine aminotransferase, total cholesterol, or triglyceride in HFD mice and OA-induced HepG2 cells. Moreover, Foxa2 overexpression decreased the expression of lipid synthesis proteins and increased fatty acid β-oxidation protein expression in the liver tissues. Furthermore, overexpression of Foxa2 downregulated the expression of p-NF-κB/NF-κB and p-IKK/IKK in OA-induced HepG2 cells. Additionally, lipopolysaccharide (NF-κB/IKK pathway activator) administration reversed the downregulation of lipid synthesis proteins and the upregulation of fatty acid β-oxidation protein. Conclusion Foxa2 expression is downregulated in NAFLD. Foxa2 ameliorated hepatic steatosis and inhibited the activation of the NF-κB/IKK signaling pathway.

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Causal Relationship between Mitochondrial Biological Function and Periodontitis: Evidence from a Mendelian Randomization Study

Zhou,

Qi,

Cao

et al. 2024

IJMS

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A growing number of studies indicate that mitochondrial dysfunction serves as a pathological mechanism for periodontitis. Therefore, this two-sample Mendelian randomization (MR) study was carried out to explore the causal associations between mitochondrial biological function and periodontitis, because the specific nature of this causal relationship remains inconclusive in existing MR studies. Inverse variance weighting, Mendelian randomization-Egger, weighted mode, simple mode, and weighted median analyses were performed to assess the causal relationships between the exposure factors and periodontitis. The results of the present study revealed a causal association between periodontitis and medium-chain specific acyl-CoA dehydrogenase (MCAD), malonyl-CoA decarboxylase (MLYCD), glutaredoxin 2 (Grx2), oligoribonuclease (ORN), and pyruvate carboxylase (PC). Notably, MCAD and MLYCD are causally linked to periodontitis, and serve as protective factors. However, Grx2, ORN, and PC function as risk factors for periodontitis. Our study established a causal relationship between mitochondrial biological function and periodontitis, and such insights may provide a promising approach for treating periodontitis via mitochondrial regulation.

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MCAD activation by empagliflozin promotes fatty acid oxidation and reduces lipid deposition in NASH

Cited by 4 publications

References 26 publications

Wnt/β-catenin signaling activation promotes lipogenesis in the steatotic liver via physical mTOR interaction

Wnt/β-catenin signaling activation promotes lipogenesis in the steatotic liver via physical mTOR interaction

Foxa2 attenuates steatosis and inhibits the NF-κB/IKK signaling pathway in nonalcoholic fatty liver disease

Causal Relationship between Mitochondrial Biological Function and Periodontitis: Evidence from a Mendelian Randomization Study

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