Nuciferine blocks MIB2-mediated CARD6 polyubiquitination and degradation in the amelioration of high fructose-induced liver lipid accumulation

Nonalcoholic fatty liver disease (NAFLD) causes significant global mortality and healthcare costs with no recommended pharmacological intervention for clinical management. Nuciferine (Nuc) is an alkaloid with aromatic rings, abundantly found in Nelumbo nucifera Gaertn. In this study, we explored the protective mechanisms of Nuc against hepatic steatosis and ferroptosis in NAFLD. High-fat diet (HFD) and healthy male ApoE −/− mice were used to induce NAFLD and a hypercholesterolemia model. Nuc was administered to the mice for four consecutive weeks from the ninth week. Various assessments, including histopathology, RNA sequencing, lipid metabolism, and ferroptosis-related protein expression, showed that Nuc alleviated hepatic steatosis and ferroptosis. We further showed that Nuc improves fatty acid accumulation and ferroptosis through the PPARα signaling pathway in mice and RSL3-treated AML-12 cells. The PPARα inhibitor GW6471 blocked Nuc's protective effects, leading to excess accumulation of iron ions. Thus, Nuc may be a potential therapeutic agent for NAFLD.

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Spatial and Single‐Cell Transcriptomics Reveals the Regional Division of the Spatial Structure of MASH Fibrosis

Li,

Yang,

Xiao

et al. 2024

Liver International

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ObjectiveTo elucidate the regional distribution of metabolic dysfunction‐associated steatohepatitis (MASH) fibrosis within the liver and to identify potential therapeutic targets for MASH fibrosis.MethodsLiver sections from healthy controls, patients with simple steatosis and MASH patients were analysed using spatial transcriptomics integrated with single‐cell RNA‐seq.ResultsSpatial transcriptomics analysis of liver tissues revealed that the fibrotic region (Cluster 9) was primarily distributed in lobules, with some fibrosis also found in the surrounding area. Integration of the single‐cell‐sequencing data set (GSE189175) showed a greater proportion of inflammatory cells (Kupffer cells and T cells) and myofibroblasts in MASH. Six genes, showing high‐ or low‐specific expression in Cluster 9, namely, ADAMTSL2, PTGDS, S100A6, PPP1R1A, ASS1 and G6PC, were identified in combination with pathology. The average expression levels of ADAMTSL2, PTGDS and S100A6 on the pathological HE staining map were positively correlated with the increase in the degree of fibrosis and aligned strongly with the distribution of fibrosis. ADAMTSL2+ myofibroblasts play a role in TNF signalling pathways and in the production of ECM structural components. Pseudotime analysis indicated that in the early stages of MASH, infiltration by T cells and Kupffer cells triggers a significant inflammatory response. Subsequently, this inflammation leads to the activation of hepatic stellate cells (HSCs), transforming them into myofibroblasts and promoting the development of liver fibrosis.ConclusionThis study is the first to characterise lineage‐specific changes in gene expression, subpopulation composition, and pseudotime analysis in MASH fibrosis and reveals potential therapeutic targets for this condition.

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Nuciferine blocks MIB2-mediated CARD6 polyubiquitination and degradation in the amelioration of high fructose-induced liver lipid accumulation

Abstract: Dietary alkaloid nuciferine isolated from the leaves of Nelumbo nucifera can ameliorate dyslipidemia and liver lipid accumulation, but the underlying mechanism remains unclear. Caspase recruitment domain protein family member 6...

Cited by 3 publications

References 46 publications

Preparation, structural characterization, and biological activities of lotus polysaccharides: A review

Preparation, structural characterization, and biological activities of lotus polysaccharides: A review

Nuciferine Alleviates High-Fat Diet- and ApoE^–/–-Induced Hepatic Steatosis and Ferroptosis in NAFLD Mice via the PPARα Signaling Pathway

Spatial and Single‐Cell Transcriptomics Reveals the Regional Division of the Spatial Structure of MASH Fibrosis

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Nuciferine blocks MIB2-mediated CARD6 polyubiquitination and degradation in the amelioration of high fructose-induced liver lipid accumulation

Abstract: Dietary alkaloid nuciferine isolated from the leaves of Nelumbo nucifera can ameliorate dyslipidemia and liver lipid accumulation, but the underlying mechanism remains unclear. Caspase recruitment domain protein family member 6...

Cited by 3 publications

References 46 publications

Preparation, structural characterization, and biological activities of lotus polysaccharides: A review

Preparation, structural characterization, and biological activities of lotus polysaccharides: A review

Nuciferine Alleviates High-Fat Diet- and ApoE–/–-Induced Hepatic Steatosis and Ferroptosis in NAFLD Mice via the PPARα Signaling Pathway

Spatial and Single‐Cell Transcriptomics Reveals the Regional Division of the Spatial Structure of MASH Fibrosis

Contact Info

Product

Resources

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Nuciferine Alleviates High-Fat Diet- and ApoE^–/–-Induced Hepatic Steatosis and Ferroptosis in NAFLD Mice via the PPARα Signaling Pathway