Dexmedetomidine ameliorates high‐fat diet‐induced nonalcoholic fatty liver disease by targeting SCD1 in obesity mice

Abstract

Fatty liver disease is one of the main hepatic complications associated with obesity. To date, there are no therapeutic drugs approved for this pathology. Insulin resistance (IR) is implicated both in pathogenesis of nonalcoholic fatty liver disease (NAFLD) and in disease progression from steatosis to nonalcoholic steatohepatitis. In this study, we have characterized effects of an α 2 ‐adrenoceptor agonist, dexmedetomidine (DEX), which can alleviate IR in hepatocytes in high‐fat diet (HFD)‐induced NAFLD mice. The NAFLD mice received a daily intraperitoneal administration of DEX (100 μg·kg ‐1 ) after 16 days exhibited lower body weight, fewer and smaller fat droplets in the liver, markedly reduced the plasma triglyceride levels, accompanied by improvement of liver damage. This inhibition of lipid accumulation activity in obese mice was associated with a robust reduction in the mRNA and protein expression of the lipogenic enzyme stearyl‐coenzyme A desaturase 1 (SCD1), which was probably mediated by the inhibition of C/EBP β, PPAR γ and C/EBP α through suppressing α 2A ‐adrenoceptor ( α 2A ‐AR ) via negative feedback. Additionally, DEX can also improve IR and inflammation by inhibiting the mitogen‐activated protein kinases (MAPK) and nuclear factor kappa beta (NFκB) signaling pathway in vivo. Our findings implicate that DEX may act as a potential anti‐steatotic drug which ameliorates obesity‐associated fatty liver and improves IR and inflammation, probably by suppressing the expression of SCD1 and the inhibition of MAPK/NFκB pathway and suggest the potential adjuvant use for the treatment of NAFLD.

Instant Dark Tea Alleviates Hyperlipidaemia in High-Fat Diet-Fed Rat: From Molecular Evidence to Redox Balance and Beyond

“…PPARγ , a nuclear receptor that acts as a ligandinducible transcription factor that regulates fat storage and glucose homeostasis, exerting antioxidant and antiinflammatory effects, is downregulated by diet-induced obesity (9,10). SCD1 is one of the downstream effectors of PPARγ , which was reported significantly induced after HFD, accompanied by lipid accumulation (11). CD36 not only acts as a free fatty acid (FFA) transporter, but also regulates FFA oxidation, lipid synthesis, VLDL secretion, inflammation, and autophagy in liver cells (12).…”

Guanabenz ameliorates disease in vanishing white matter mice in contrast to sephin1

“…GBZ increases body weight gain in VWM mice, but less so than seen with previous successful ISR‐ modulating treatments 13,14 . Daily GBZ‐treated WT animals show a reduction in body weight gain probably due to GBZ's sedative or hypothermic effects 43–45 . These effects have probably curbed a GBZ‐induced body weight gain in VWM mice, obscuring its full beneficial potential on weight gain.…”

“…13,14 Daily GBZ-treated WT animals show a reduction in body weight gain probably due to GBZ's sedative or hypothermic effects. [43][44][45] These effects have probably curbed a GBZ-induced body weight gain in VWM mice, obscuring its full beneficial potential on weight gain. The study shows GBZ's beneficial effect on VWM brain pathology hallmarks for the daily dosing schedule.…”

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“… 2021 ), liver function, and liver levels (Tao et al. 2021 ) in addition to oil red and H&E staining (Ben Hamad Bouhamed et al. 2019 ; Yang et al.…”