Targeting alkaline ceramidase 3 alleviates the severity of nonalcoholic steatohepatitis by reducing oxidative stress

Wang, Kai; Li, Chuanjiang; Lin, Xinxin; Sun, Hang; Xu, Ruijuan; Li, Qingping; Wei, Yiran; Li, Yiyi; Qian, Jiang; Liu, Cuiting; Zhang, Qifan; Yu, Shanshan; Cui, Zhonglin; Huang, Xixin; Zhu, Biqing; Zhou, Jie; Mao, Cungui

doi:10.1038/s41419-019-2214-9

Cited by 29 publications

(22 citation statements)

References 47 publications

(63 reference statements)

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“…Oxidative stress, which can promote the injury of hepatocytes, has been proved to be a crucial pathological event for the progression of NASH (Wang et al, 2020). In this research, we found that MCD diet feeding significantly increased the levels of MDA in the liver, while PEA treatment obviously attenuated this elevation.…”

Section: Discussionmentioning

confidence: 50%

Micronized Palmitoylethanolamide Ameliorates Methionine- and Choline-Deficient Diet–Induced Nonalcoholic Steatohepatitis via Inhibiting Inflammation and Restoring Autophagy

Ying

Yao

et al. 2021

Front. Pharmacol.

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Nonalcoholic steatohepatitis (NASH) has become one of the serious causes of chronic liver diseases, characterized by hepatic steatosis, hepatocellular injury, inflammation and fibrosis, and lack of efficient therapeutic agents. Palmitoylethanolamide (PEA) is an endogenous bioactive lipid with various pharmacological activities, including anti-inflammatory, analgesic, and neuroprotective effects. However, the effect of PEA on nonalcoholic steatohepatitis is still unknown. Our study aims to explore the potential protective role of PEA on NASH and to reveal the underlying mechanism. In this study, the C57BL/6 mice were used to establish the NASH model through methionine- and choline-deficient (MCD) diet feeding. Here, we found that PEA treatment significantly improved liver function, alleviated hepatic pathological changes, and attenuated the lipid accumulation and hepatic fibrosis in NASH mice induced by MCD diet feeding. Mechanistically, the anti-steatosis effect of PEA may be due to the suppressed expression of ACC1 and CD36, elevated expression of PPAR-α, and the phosphorylation levels of AMPK. In addition, hepatic oxidative stress was greatly inhibited in MCD-fed mice treated with PEA via enhancing the expression and activities of antioxidant enzymes, including GSH-px and SOD. Moreover, PEA exerted a clear anti-inflammatory effect though ameliorating the expression of inflammatory mediators and suppressing the NLRP3 inflammasome pathway activation. Furthermore, the impaired autophagy in MCD-induced mice was reactivated with PEA treatment. Taken together, our research suggested that PEA protects against NASH through the inhibition of inflammation and restoration of autophagy. Thus, PEA may represent an efficient therapeutic agent to treat NASH.

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Section: Discussionmentioning

confidence: 50%

Micronized Palmitoylethanolamide Ameliorates Methionine- and Choline-Deficient Diet–Induced Nonalcoholic Steatohepatitis via Inhibiting Inflammation and Restoring Autophagy

Ying

Yao

et al. 2021

Front. Pharmacol.

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“…A very recent study showed that deficiency of ACER3 alleviates the pathogenesis of NASH by regulating the hepatic levels of C18:1‐ceramide. ( 30 ) It is intriguing that NcDase activity influences the composition of MUFAs and the reduction of particularly FA18:1 n‐9 and FA16:1 in the total lipid fraction in TG, CE, and PL fractions in NcDase −/− mice (Fig. 3).…”

Section: Discussionmentioning

confidence: 99%

Neutral Ceramidase Mediates Nonalcoholic Steatohepatitis by Regulating Monounsaturated Fatty Acids and Gut IgA+ B Cells

Sun

Chen

et al. 2021

Hepatology

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Background and Aims Nonalcoholic steatohepatitis (NASH) is associated with obesity and an increased risk for liver cirrhosis and cancer. Neutral ceramidase (NcDase), which is highly expressed in the intestinal brush border of the small intestine, plays a critical role in digesting dietary sphingolipids (ceramide) to regulate the balance of sphingosine and free fatty acids. It remains unresolved whether obesity‐associated alteration of NcDase contributes to the manifestation of NASH. Here, we revealed that NcDase deficiency in murine models of NASH prevents hepatic inflammation and fibrosis but not steatosis. Approach and Results NcDase−/− mice display reduced stearoyl‐CoA desaturase (SCD) 1 expression with a compositional decrease of monounsaturated fatty acids (MUFAs) under the different dietary conditions. We further found that NcDase is a functional regulator of intestinal B cells and influences the abundance and quality of the secretory IgA response toward commensal bacteria. Analysis of composition of the gut microbiota found that Clostridiales colonization was increased in NcDase−/− mice. The colonization of germ‐free mice with gut microbiota from NcDase−/− mice resulted in a greater decrease in the expression of SCD1 and the level of MUFAs in the liver relative to gut microbiota from wild‐type littermates, which are associated with the alternation of IgA‐bound bacteria, including increase of Ruminococcaceae and reduction of Desulfovibrio. Mechanistically, NcDase is a crucial link that controls the expression of SCD1 and MUFA‐mediated activation of the Wnt/β‐catenin. Very importantly, our experiments further demonstrated that Wnt3a stimulation can enhance the activity of NcDase in hepatocytes. Conclusions Thus, the NcDase‐SCD1‐Wnt feedback loop promotes the diet‐induced steatohepatitis and fibrosis through the regulation of intestinal IgA+ immune cells.

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“…For example, ultraviolet and H 2 O 2 treatment generates ceramide, which activates AMPK [58], while short-chain ceramides inhibit Nrf2 activation [34], and knock out of acid ceramidase 3 augments C18:1-ceramide levels, which alleviates early inflammation, oxidative stress, and fibrosis in a mouse model of NASH [59]. It has also been suggested that ceramide-activated AMPK can limit nutrient-induced stress and autophagy [60].…”

Section: Discussionmentioning

confidence: 99%

Exogenous Liposomal Ceramide-C6 Ameliorates Lipidomic Profile, Energy Homeostasis, and Anti-Oxidant Systems in NASH

Zanieri

Levi

Montefusco

et al. 2020

Cells

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In non-alcoholic steatohepatitis (NASH), many lines of investigation have reported a dysregulation in lipid homeostasis, leading to intrahepatic lipid accumulation. Recently, the role of dysfunctional sphingolipid metabolism has also been proposed. Human and animal models of NASH have been associated with elevated levels of long chain ceramides and pro-apoptotic sphingolipid metabolites, implicated in regulating fatty acid oxidation and inflammation. Importantly, inhibition of de novo ceramide biosynthesis or knock-down of ceramide synthases reverse some of the pathology of NASH. In contrast, cell permeable, short chain ceramides have shown anti-inflammatory actions in multiple models of inflammatory disease. Here, we investigated non-apoptotic doses of a liposome containing short chain C6-Ceramide (Lip-C6) administered to human hepatic stellate cells (hHSC), a key effector of hepatic fibrogenesis, and an animal model characterized by inflammation and elevated liver fat content. On the basis of the results from unbiased liver transcriptomic studies from non-alcoholic fatty liver disease patients, we chose to focus on adenosine monophosphate activated kinase (AMPK) and nuclear factor-erythroid 2-related factor (Nrf2) signaling pathways, which showed an abnormal profile. Lip-C6 administration inhibited hHSC proliferation while improving anti-oxidant protection and energy homeostasis, as indicated by upregulation of Nrf2, activation of AMPK and an increase in ATP. To confirm these in vitro data, we investigated the effect of a single tail-vein injection of Lip-C6 in the methionine-choline deficient (MCD) diet mouse model. Lip-C6, but not control liposomes, upregulated phospho-AMPK, without inducing liver toxicity, apoptosis, or exacerbating inflammatory signaling pathways. Alluding to mechanism, mass spectrometry lipidomics showed that Lip-C6-treatment reversed the imbalance in hepatic phosphatidylcholines and diacylglycerides species induced by the MCD-fed diet. These results reveal that short-term Lip-C6 administration reverses energy/metabolic depletion and increases protective anti-oxidant signaling pathways, possibly by restoring homeostatic lipid function in a model of liver inflammation with fat accumulation.

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Targeting alkaline ceramidase 3 alleviates the severity of nonalcoholic steatohepatitis by reducing oxidative stress

Cited by 29 publications

References 47 publications

Micronized Palmitoylethanolamide Ameliorates Methionine- and Choline-Deficient Diet–Induced Nonalcoholic Steatohepatitis via Inhibiting Inflammation and Restoring Autophagy

Micronized Palmitoylethanolamide Ameliorates Methionine- and Choline-Deficient Diet–Induced Nonalcoholic Steatohepatitis via Inhibiting Inflammation and Restoring Autophagy

Neutral Ceramidase Mediates Nonalcoholic Steatohepatitis by Regulating Monounsaturated Fatty Acids and Gut IgA+ B Cells

Exogenous Liposomal Ceramide-C6 Ameliorates Lipidomic Profile, Energy Homeostasis, and Anti-Oxidant Systems in NASH

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