Time-Dependent Changes in Hepatic Sphingolipid Accumulation and PI3K/Akt/mTOR Signaling Pathway in a Rat Model of NAFLD

Sztolsztener, Klaudia; Konstantynowicz-Nowicka, Karolina; Harasim-Symbor, Ewa; Chabowski, Adrian

doi:10.3390/ijms222212478

Cited by 13 publications

(11 citation statements)

References 41 publications

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“…Sphingolipid signaling pathway is associated with fat accumulation ( 28 ). Inhibiting glycosphingolipid biosynthesis decreased atherosclerosis by inhibiting several enzymes involved in sphingolipid synthesis ( 29 ).…”

Section: Discussionmentioning

confidence: 99%

Untargeted lipidomics and metagenomics reveal the mechanism of aspirin eugenol ester relieving hyperlipidemia in ApoE−/− mice

Liu

et al. 2022

Front. Nutr.

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Hyperlipidemia is induced by abnormal lipid metabolism, which can cause the occurrence of cardiovascular diseases and lead to grievous injury to health. Studies showed that AEE had a significant therapeutic effect on hyperlipidemia and is likely to be associated with the up-regulation of cholesterol 7-alpha hydroxylase (CYP7A1), the key enzyme for cholesterol conversion to bile acids, but no research confirmed whether the effect of AEE on hyperlipidemia was related to the gut microbiota and liver lipids. At the same time, more and more studies have shown that gut microbiota and lipids are closely related to hyperlipidemia. Hence, in this study, we investigated the effects of AEE on liver lipids through LC-MS-based untargeted lipidomics and the effects of AEE on gut microbiota based on cecal contents metagenomics by Illumina sequencing in HFD-induced hyperlipidemia ApoE−/− mice at the overall level. The results of lipidomics showed that AEE relieved hyperlipidemia by decreasing the concentration of 10 PEs and 12 SMs in the liver and regulating the pathways of glycerophospholipid metabolic pathway, sphingolipid signaling pathway, and NF-kB signaling pathway. The results of metagenomics concluded that AEE treatment changed the composition of gut microbiota and regulated the functions of lipid transport and metabolism, as well as the metabolism of bile acids and secondary bile acids. The results of the joint analysis between lipidomics and metagenomics showed that the abundance of Verrucomicrobia, Verrucomicrobiales, Candidatus_Gastranaerophilales, and Candidatus_Melainabacteria was significantly positively correlated with the concentration of SM (d18:1/18:0) and PE (16:0/18:1) in the process of AEE alleviating hyperlipidemia in mice. In conclusion, these results suggested that the effect of AEE on hyperlipidemia was closely related to the gut microbiota by the change of bile acids and liver lipids.

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Section: Discussionmentioning

confidence: 99%

Untargeted lipidomics and metagenomics reveal the mechanism of aspirin eugenol ester relieving hyperlipidemia in ApoE−/− mice

Liu

et al. 2022

Front. Nutr.

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“…VLCFA breakdown occurs in the peroxisome and is required for the synthesis of plasmalogens [ 35 ]. Nervonic acid is mainly stored in hepatic sphingolipids, which are very abundant in the mouse liver [ 12 , 14 , 39 , 40 ]. Indeed, SM d42:2, which consists of the 18-carbon ceramide backbone being sphingosine and a VLCFA of 24 carbons, consistent with nervonic acid (FA 24:1), was elevated in relative abundance in HFCS-HF versus HFCO-HF offspring livers ( p = 0.029, Figure 5 G).…”

Section: Resultsmentioning

confidence: 99%

Prenatal Choline Supplement in a Maternal Obesity Model Modulates Offspring Hepatic Lipidomes

et al. 2023

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Maternal obesity during pregnancy adversely impacts offspring health, predisposing them to chronic metabolic diseases characterized by insulin resistance, dysregulated macronutrient metabolism, and lipid overload, such as metabolic-associated fatty liver disease (MAFLD). Choline is a semi-essential nutrient involved in lipid and one-carbon metabolism that is compromised during MAFLD progression. Here, we investigated under high-fat (HF) obesogenic feeding how maternal choline supplementation (CS) influenced the hepatic lipidome of mouse offspring. Our results demonstrate that maternal HF+CS increased relative abundance of a subclass of phospholipids called plasmalogens in the offspring liver at both embryonic day 17.5 and after 6 weeks of postnatal HF feeding. Consistent with the role of plasmalogens as sacrificial antioxidants, HF+CS embryos were presumably protected with lower oxidative stress. After postnatal HF feeding, the maternal HF+CS male offspring also had higher relative abundance of both sphingomyelin d42:2 and its side chain, nervonic acid (FA 24:1). Nervonic acid is exclusively metabolized in the peroxisome and is tied to plasmalogen synthesis. Altogether, this study demonstrates that under the influence of obesogenic diet, maternal CS modulates the fetal and postnatal hepatic lipidome of male offspring, favoring plasmalogen synthesis, an antioxidative response that may protect the mouse liver from damages due to HF feeding.

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“…In the presence of excess energy, excessive intake of saturated fatty acids increases plasma and intrahepatic ceramide levels more than polyunsaturated fatty acids [83][84][85]. In the high-fat-fed mice model, the level of intrahepatic ceramides deposition in mice was significantly increased compared to the control group [86], implying that using different dietary patterns could regulate the level of ceramides. In addition, Dong et al found that compared with control mice, hyperhomocysteinemia (HHcy) mice exhibited hepatic steatosis with a notable increase in ceramiderelated metabolites and subsequent upregulation of ceramide synthesis genes.…”

Section: Roles Of Ceramides In Nafldmentioning

confidence: 98%

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

Zhu¹,

Huai²,

Zhang³

et al. 2023

Int. J. Biol. Sci.

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Non-alcoholic fatty liver disease (NAFLD), as one of the main causes of chronic liver disease worldwide, encompasses a spectrum of liver conditions that are not caused by other etiology, such as overt alcohol consumption, from simple steatosis to more aggressive non-alcoholic steatohepatitis (NASH) that involves liver inflammation and fibrosis, and to the lethal cirrhosis that may result in liver cancer and liver failure. The molecular mechanisms governing the transition from steatosis to NASH remain not fully understood, but the hepatic lipidome is extensively altered in the setting of steatosis and steatohepatitis, which also correlate with disease progression. With the tremendous advancement in the field of lipidomics in last two decades, a better understanding of the specific role of sphingolipids in fatty liver disease has taken shape. Among the numerous lipid subtypes that accumulate, ceramides are particularly impactful. On the one hand, excessive ceramides deposition in the liver cause hepatic steatosis. On the other hand, ceramides as lipotoxic lipid have significant effects on hepatic inflammation, apoptosis and insulin resistance that contribute to NAFLD. In this review, we summarize and evaluate current understanding of the multiple roles of ceramides in the onset of fatty liver disease and the pathogenic mechanisms underlying their effects, and we also discuss recent advances and challenges in pharmacological interventions targeting ceramide metabolism for the treatment of NAFLD.

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Time-Dependent Changes in Hepatic Sphingolipid Accumulation and PI3K/Akt/mTOR Signaling Pathway in a Rat Model of NAFLD

Cited by 13 publications

References 41 publications

Untargeted lipidomics and metagenomics reveal the mechanism of aspirin eugenol ester relieving hyperlipidemia in ApoE−/− mice

Untargeted lipidomics and metagenomics reveal the mechanism of aspirin eugenol ester relieving hyperlipidemia in ApoE−/− mice

Prenatal Choline Supplement in a Maternal Obesity Model Modulates Offspring Hepatic Lipidomes

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

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