Insights into the roles and pathomechanisms of ceramide and sphigosine-1-phosphate in nonalcoholic fatty liver disease

Zhu, Cheng; Huai, Qian; Zhang, Xu; Dai, Hanren; Li, Xiaolei; Wang, Hua

doi:10.7150/ijbs.78525

Cited by 21 publications

(11 citation statements)

References 179 publications

(188 reference statements)

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“…Ceramides are central to sphingolipid metabolism and are structural precursors for sphingolipid biosynthesis 22 . It has been demonstrated in various animal models that ceramides promote NASH/NAFLD pathology, including steatosis, inflammation, and fibrosis through the induction of insulin resistance, increased oxidative stress, and increased apoptosis 23‐31 . Furthermore, S1P, a sphingolipid metabolite downstream of ceramide, leads to HSC activation and the progression of liver fibrosis via S1P receptors 32‐34 .…”

Section: Discussionmentioning

confidence: 99%

Novel oral SPT inhibitor CH5169356 inhibits hepatic stellate cell activation and ameliorates hepatic fibrosis in mouse models of non‐alcoholic steatohepatitis (NASH)

Hada¹,

Katsume²,

Kawasaki³

et al. 2023

Pharmacology Res & Perspec

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Ceramide is a central molecule of sphingolipid metabolism and is involved in the development of non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH). It has already been reported that the inhibition of serine palmitoyltransferase (SPT), the rate-limiting enzyme in the sphingolipid biosynthetic pathway, has an inhibitory effect on hepatic lipidosis, but its effect on severe hepatic fibrosis is not clear.In this study, we examined whether a SPT inhibitor could suppress the activation of hepatic stellate cells (HSC) and ameliorate the progression of NASH. Effects on sphingolipid metabolism and HSC activation marker genes by NA808, a SPT inhibitor, were evaluated in an immortalized HSC cell line (E14C12). NA808 decreased sphingolipid synthesis and the expression of α-smooth muscle actin (α-SMA) and collagen 1A1 mRNA in HSC. We identified a novel oral SPT inhibitor, CH5169356, which is a prodrug of NA808. CH5169356 was administered in the Ath+HF model, a NASH mouse model with liver fibrosis induced by atherogenic and high-fat content diets.CH5169356 showed a significant decrease in the expression of α-SMA and collagen 1A1 mRNA in the liver and an inhibition of liver fibrosis progression. CH5169356 was also evaluated in a Stelic animal model (STAM), a NASH mouse model induced through a different mechanism than that of the Ath+HF model, and showed a significant antifibrotic effect. In conclusion, CH5169356 could inhibit the progression of hepatic fibrosis in the pathogenesis of NASH by suppressing HSC activation, suggesting that CH5169356 would be a potential oral NASH therapeutic agent.

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Section: Discussionmentioning

confidence: 99%

Novel oral SPT inhibitor CH5169356 inhibits hepatic stellate cell activation and ameliorates hepatic fibrosis in mouse models of non‐alcoholic steatohepatitis (NASH)

Hada¹,

Katsume²,

Kawasaki³

et al. 2023

Pharmacology Res & Perspec

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“…Elevated levels of ceramide also activate inflammatory responses of Kupffer cells and promote the production of inflammatory cytokines and chemokines, contributing to liver inflammation and injury. In hepatic sinusoidal endothelial cells, ceramide-mediated endothelial dysfunction may contribute to liver injury, fibrosis, and impaired liver regeneration [ 21 , 22 ]. The sphingolipid pathway also plays a critical role in regulating lymphocyte function in the liver, contributing to both immune surveillance and immune-mediated liver disease ( Figure 2 ) [ 23 ].…”

Section: Metabolism and Physiological Functions In Sphingolipidsmentioning

confidence: 99%

Critical Roles of the Sphingolipid Metabolic Pathway in Liver Regeneration, Hepatocellular Carcinoma Progression and Therapy

Nojima,

Shimizu,

Murakami

et al. 2024

Cancers

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The sphingolipid metabolic pathway, an important signaling pathway, plays a crucial role in various physiological processes including cell proliferation, survival, apoptosis, and immune regulation. The liver has the unique ability to regenerate using bioactive lipid mediators involving multiple sphingolipids, including ceramide and sphingosine 1-phosphate (S1P). Dysregulation of the balance between sphingomyelin, ceramide, and S1P has been implicated in the regulation of liver regeneration and diseases, including liver fibrosis and hepatocellular carcinoma (HCC). Understanding and modulating this balance may have therapeutic implications for tumor proliferation, progression, and metastasis in HCC. For cancer therapy, several inhibitors and activators of sphingolipid signaling, including ABC294640, SKI-II, and FTY720, have been discussed. Here, we elucidate the critical roles of the sphingolipid pathway in the regulation of liver regeneration, fibrosis, and HCC. Regulation of sphingolipids and their corresponding enzymes may considerably influence new insights into therapies for various liver disorders and diseases.

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“…Sphingolipid ceramide 16:0 directly decreases mitochondrial FAO in hepatocytes from steatotic mice, accompanied by reduced hepatic insulin signaling and hyperglycemia [ 81 ]. Notably, the data from cohorts of NASH patients presented a strong correlation between serum and liver ceramide levels [ 82 ]. Exacerbated hepatic ceramide content is linked to diminished mitochondrial oxidative capacity [ 83 ].…”

Section: Mitochondrial (Dys)function In Nafldmentioning

confidence: 99%

From Non-Alcoholic Fatty Liver to Hepatocellular Carcinoma: A Story of (Mal)Adapted Mitochondria

Amorim

Magalhães

Borges

et al. 2023

Biology

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Non-alcoholic fatty liver disease (NAFLD) is a global pandemic affecting 25% of the world’s population and is a serious health and economic concern worldwide. NAFLD is mainly the result of unhealthy dietary habits combined with sedentary lifestyle, although some genetic contributions to NAFLD have been documented. NAFLD is characterized by the excessive accumulation of triglycerides (TGs) in hepatocytes and encompasses a spectrum of chronic liver abnormalities, ranging from simple steatosis (NAFL) to steatohepatitis (NASH), significant liver fibrosis, cirrhosis, and hepatocellular carcinoma. Although the molecular mechanisms that cause the progression of steatosis to severe liver damage are not fully understood, metabolic-dysfunction-associated fatty liver disease is strong evidence that mitochondrial dysfunction plays a significant role in the development and progression of NAFLD. Mitochondria are highly dynamic organelles that undergo functional and structural adaptations to meet the metabolic requirements of the cell. Alterations in nutrient availability or cellular energy needs can modify mitochondria formation through biogenesis or the opposite processes of fission and fusion and fragmentation. In NAFL, simple steatosis can be seen as an adaptive response to storing lipotoxic free fatty acids (FFAs) as inert TGs due to chronic perturbation in lipid metabolism and lipotoxic insults. However, when liver hepatocytes’ adaptive mechanisms are overburdened, lipotoxicity occurs, contributing to reactive oxygen species (ROS) formation, mitochondrial dysfunction, and endoplasmic reticulum (ER) stress. Impaired mitochondrial fatty acid oxidation, reduction in mitochondrial quality, and disrupted mitochondrial function are associated with a decrease in the energy levels and impaired redox balance and negatively affect mitochondria hepatocyte tolerance towards damaging hits. However, the sequence of events underlying mitochondrial failure from steatosis to hepatocarcinoma is still yet to be fully clarified. This review provides an overview of our understanding of mitochondrial adaptation in initial NAFLD stages and highlights how hepatic mitochondrial dysfunction and heterogeneity contribute to disease pathophysiology progression, from steatosis to hepatocellular carcinoma. Improving our understanding of different aspects of hepatocytes’ mitochondrial physiology in the context of disease development and progression is crucial to improving diagnosis, management, and therapy of NAFLD/NASH.

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Insights into the roles and pathomechanisms of ceramide and sphigosine-1-phosphate in nonalcoholic fatty liver disease

Cited by 21 publications

References 179 publications

Novel oral SPT inhibitor CH5169356 inhibits hepatic stellate cell activation and ameliorates hepatic fibrosis in mouse models of non‐alcoholic steatohepatitis (NASH)

Novel oral SPT inhibitor CH5169356 inhibits hepatic stellate cell activation and ameliorates hepatic fibrosis in mouse models of non‐alcoholic steatohepatitis (NASH)

Critical Roles of the Sphingolipid Metabolic Pathway in Liver Regeneration, Hepatocellular Carcinoma Progression and Therapy

From Non-Alcoholic Fatty Liver to Hepatocellular Carcinoma: A Story of (Mal)Adapted Mitochondria

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