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Transcriptomic Analysis Reveals the Protective Effects of Empagliflozin on Lipid Metabolism in Nonalcoholic Fatty Liver Disease.

ABSTRACT: Empagliflozin is a novel type of sodium-glucose cotransporter two inhibitor with diverse beneficial effects in the treatment of nonalcoholic fatty liver disease (NAFLD). Although empagliflozin impacts NAFLD by regulating lipid metabolism, the underlying mechanism has not been fully elucidated. In this study, we investigated transcriptional regulation pathways affected by empagliflozin in a mouse model of NAFLD. In this study, NAFLD was established in male C57BL/6J mice by administration of a high-fat diet; it was then treated with empagliflozin and whole transcriptome analysis was conducted. Gene expression levels detected by transcriptome analysis were then verified by quantitative real-time polymerase chain reaction, protein levels detected by Western Blot. Differential expression genes screened from RNA-Seq data were enriched in lipid metabolism and synthesis. The Gene Set Enrichment Analysis (GSEA) results showed decreased lipid synthesis and improved lipid metabolism. Empagliflozin improved NAFLD through enhanced triglyceride transfer, triglyceride lipolysis and microsomal mitochondrial β-oxidation. This study provides new insights concerning the mechanisms by which sodium-glucose cotransporter two inhibitors impact NAFLD, particularly in terms of liver lipid metabolism. The lipid metabolism-related genes identified in this experiment provide robust evidence for further analyses of the mechanism by which empagliflozin impacts NAFLD.

SUBMITTER: Ma Y

PROVIDER: S-EPMC8724565 | biostudies-literature |

REPOSITORIES: biostudies-literature

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PAR2 controls cholesterol homeostasis and lipid metabolism in nonalcoholic fatty liver disease.

Project description:OBJECTIVE:Increases in hepatic and plasma cholesterol occur in patients with nonalcoholic fatty liver disease (NAFLD), although the reason for this is not well understood. We investigated whether Protease-Activated Receptor 2 (PAR2) plays a role in cholesterol and lipid homeostasis in NAFLD. METHODS:Human liver biopsies (n = 108) were quantified for PAR2 expression from NAFLD cases randomly selected and stratified by liver fibrosis stage, the primary predictor for clinical outcomes, while controlling for age, gender, and BMI between fibrosis groups. Demographic data and laboratory studies on plasma samples were obtained within 6 months of liver biopsy. Wild-type and PAR2-KO (C57BL/6 F2rl1-/-) mice were fed either normal or high fat diet for 16 weeks and plasma and liver assayed for lipids and soluble metabolites. RESULTS:Severity of NAFLD and plasma cholesterol levels significantly correlated with hepatocyte PAR2 expression in NAFLD patients. Conversely, PAR2 deficiency in mice resulted in reduced expression of key hepatic genes involved in cholesterol synthesis, a 50% drop in plasma and total liver cholesterol, and induced a reverse cholesterol transport system that culminated in 25% higher fecal bile acid output. PAR2-deficient mice exhibited enhanced fatty acid β-oxidation with a ketogenic shift and an unexpected increase in liver glycogenesis. Mechanistic studies identified Gi-Jnk1/2 as key downstream effectors of protease-activated PAR2 in the regulation of lipid and cholesterol homeostasis in liver. CONCLUSIONS:These data indicate that PAR2 may be a new target for the suppression of plasma cholesterol and hepatic fat accumulation in NAFLD and related metabolic conditions.

| S-EPMC6742970 | biostudies-literature

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

Project description: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.

| S-EPMC9483033 | biostudies-literature

Liraglutide Attenuates Nonalcoholic Fatty Liver Disease through Adjusting Lipid Metabolism via SHP1/AMPK Signaling Pathway.

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| S-EPMC6545813 | biostudies-literature

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| S-EPMC8581616 | biostudies-literature

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| S-EPMC3988578 | biostudies-literature

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| S-EPMC6430223 | biostudies-literature

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| S-EPMC5396354 | biostudies-literature

Spatial Systems Lipidomics Reveals Nonalcoholic Fatty Liver Disease Heterogeneity.

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| S-EPMC5906754 | biostudies-literature

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| S-EPMC6957964 | biostudies-literature

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