Honokiol attenuates lipotoxicity in hepatocytes via activating SIRT3-AMPK mediated lipophagy

Abstract

Background Non-alcoholic fatty liver disease (NAFLD) is characterized by ectopic accumulation of triglycerides in the liver. Emerging evidence has demonstrated that lipophagy regulates lipid mobilization and energy homeostasis in the liver. Sirtuin 3 (SIRT3), a mitochondrial NAD+-dependent deacetylase, modulates the activities of several substrates involving in autophagy and energy metabolism. Honokiol (HK) is a natural lignan from the plants of Magnolia genus that exhibits potent liver protective property. Methods AML12 was challenged with 500 μM palmitic acid and 250 μM oleic acid mixture solution to induce lipotoxicity. C57BL/6J mice were fed with a choline-deficient high fat diet (CDHFD) to generate liver steatosis. The expression of autophagy-related and AMP-activated protein kinase (AMPK) pathway proteins was evaluated by Western blotting and immunofluorescence staining. Intracellular lipid accumulation was validated by Nile red staining. Molecular docking analysis was performed on AutoDock 4.2. Results HK (5 and 10 μM) was found to attenuate lipid accumulation through promoting SIRT3-AMPK-mediated autophagy, mainly on lipid droplets. HK had hydrophobic interaction with amino acid residues (PHE294, GLU323 and VAL324) and NAD+. Moreover, HK improved mitochondrial function to enhance lipolysis, through decreasing the acetylated long-chain acyl-CoA dehydrogenase level. In CDHFD-fed mice, HK (2.5 and 10 mg/Kg) treatment obviously prevented lipid accumulation in the liver. And co-treatment of the AMPK inhibitor, Compound C, almost abolished the above changes. Conclusions These results suggest that HK could ameliorate lipotoxicity in hepatocytes by activating SIRT3-AMPK-lipophagy axis, which might be a potential therapeutic agent against NAFLD.

Natural-Product-Mediated Autophagy in the Treatment of Various Liver Diseases

“…More red puncta were formed in the mRFP-GFP-LC3 assay, the colocalization of mRFP-LC3 and Nile red (indicated LDs) was increased, the P/O-induced shrinkage in the ratio of LC3-II/LC3-I and Beclin1 level, and the elevation of P62 were all reversed in HK-treated cells in comparison with the control. In addition, the LD fraction was isolated and the enrichment of LC3-II, Beclin1 and decreased P62 were observed in LD fractions rather than in whole cell homogenates after HK treatment, which further confirmed the lipophagy activation [ 90 ]. In another study, the ethanol extract of Cyclocarya paliurus (CPE) was reported to effectively induce lipid clearance associated with increased autophagy.…”

Nobiletin mitigates NAFLD via lipophagy and inflammation

“…57 On the other hand, an improvement in the lipophagy pathway was reported as an effective method to alleviate the progression of NAFLD. For example, the effect of honokiol to ameliorate lipotoxicity in hepatocytes was through activating SIRT3-AMPK mediated lipophagy, 58 and P2X7 improved hepatic steatosis by elevating the lipophagy level. 59 Moreover, the effect of NOB on activating lipophagy was reported in some diseases, such as pulmonary fibrosis 60 and ovarian cancer.…”

Lipidomics reveals the potential mechanism of honokiol against adenine-induced chronic kidney disease

“…Previous studies have reported that HKL can regulate lipid metabolism through other mechanisms. Liu et al found that HKL could ameliorate lipotoxicity in hepatocytes by activating SIRT3-AMPK mediated lipophagy (Liu et al, 2021). Additional study suggested that HKL could block fatty acid synthesis by inhibiting sterol Frontiers in Pharmacology frontiersin.org regulatory element-binding protein-1c (SREBP-1c) maturation and the induction of lipogenic proteins, stearoyl-CoA desaturase-1 (SCD-1) and fatty acid synthase (FASN) (Seo et al, 2015).…”

“…However, the role and mechanism of HKL in treating CKD remain to be determined. Previously, HKL was reported to attenuate lipid accumulation and lipotoxicity in hepatocytes to protect against non alcoholic fatty liver disease (Seo et al, 2015;Liu et al, 2021). In mice with cisplatin-induced acute kidney injury, HKL could improve fatty acid oxidation and renal function and reduce fatty acid deposition (Li et al, 2020).…”