Bile acids and sphingolipids in non-alcoholic fatty liver disease

Jackson, Kasey L.; Way, Grayson W; Zhou, Huiping

doi:10.1097/cm9.0000000000002156

Cited by 16 publications

(9 citation statements)

References 74 publications

(260 reference statements)

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“…[48,49] In recent years, there is growing evidence that sphingolipid metabolism is implicated in several pathophysiological processes of NAFLD, including regulation of hepatic lipid metabolism, inhibition of inflammation and improvement of insulin resistance. [50,51] However, the connection between sphingolipid metabolism and the biological and clinical manifestations of NAFLD is not fully clarified. Consequently, understanding the specific mechanisms of SMRGs involving in NAFLD, and identifying targeted interventions, is vital for refining diagnostic criteria and therapeutic strategies.…”

Section: Discussionmentioning

confidence: 99%

Diagnostic value of sphingolipid metabolism-related genes CD37 and CXCL9 in nonalcoholic fatty liver disease

Zhang,

Wang,

Jiang

2024

Medicine

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The development of nonalcoholic fatty liver disease (NAFLD) has been reported to be caused by sphingolipid family inducing insulin resistance, mitochondrial dysfunction, and inflammation, which can be regulated by multiple sphingolipid metabolic pathways. This study aimed to explore the molecular mechanism of crucial sphingolipid metabolism related genes (SMRGs) in NAFLD. Firstly, the datasets (GSE48452, GSE126848, and GSE63067) from the Gene Expression Omnibus database and sphingolipid metabolism genes (SMGs) from previous research were collected for this study. The differentially expressed genes (DEGs) between different NAFLD and controls were acquired through “limma,” and the SMRGs were authenticated via weighted gene co-expression network analysis (WGCNA). After overlapping the DEGs and SMRGs, the causality between the intersection genes (DE-SMRGs) and NAFLD was explored to sort out the candidate biomarkers by Mendelian randomization (MR) study. The receiver operating characteristic (ROC) curves of candidate biomarkers in GSE48452 and GSE126848 were yielded to determine the biomarkers, followed by the nomogram construction and enrichment analysis. Finally, the immune infiltration analysis, the prediction of transcription factors (TFs) and drugs targeting biomarkers were put into effect. A total of 23 DE-SMRGs were acquired based on the differential analysis and weighted gene co-expression network analysis (WGCNA), of which 3 DE-SMRGs (CD37, CXCL9 and IL7R) were picked out for follow-up analysis through univariate and multivariate MR analysis. The values of area under ROC curve of CD37 and CXCL9 were >0.7 in GSE48452 and GSE126848, thereby being regarded as biomarkers, which were mainly enriched in amino acid metabolism. With respect to the Spearman analysis between immune cells and biomarkers, CD37 and CXCL9 were significantly positively associated with M1 macrophages (P < .001), whose proportion was observably higher in NAFLD patients compared with controls. At last, TFs (ZNF460 and ZNF384) of CD37 and CXCL9 and a total of 79 chemical drugs targeting CD37 and CXCL9 were predicted. This study mined the pivotal SMRGs, CD37 and CXCL9, and systematically explored the mechanism of action of both biomarkers based on the public databases, which could tender a fresh reference for the clinical diagnosis and therapy of NAFLD.

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Section: Discussionmentioning

confidence: 99%

Diagnostic value of sphingolipid metabolism-related genes CD37 and CXCL9 in nonalcoholic fatty liver disease

Zhang,

Wang,

Jiang

2024

Medicine

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“…The upregulated Smpd3 expression was supported by increased nSMAse2 activity in the livers of HFD-fed mice. Sphingolipids are implicated in a wide variety of biological functions such as inflammation, immune response, cell cycle, adhesion, and migration [ 40 , 41 ]. Ceramide, a core product of sphingolipid metabolism, is known to play a role in hepatocellular apoptosis and fibrosis [ 3 , 42 ].…”

Section: Discussionmentioning

confidence: 99%

Neutral Sphingomyelinase 2 Inhibition Limits Hepatic Steatosis and Inflammation

Al-Rashed,

Arefanian,

Madhoun

et al. 2024

Cells

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Non-alcoholic fatty liver disease (NAFLD) is manifested by hepatic steatosis, insulin resistance, hepatocyte death, and systemic inflammation. Obesity induces steatosis and chronic inflammation in the liver. However, the precise mechanism underlying hepatic steatosis in the setting of obesity remains unclear. Here, we report studies that address this question. After 14 weeks on a high-fat diet (HFD) with high sucrose, C57BL/6 mice revealed a phenotype of liver steatosis. Transcriptional profiling analysis of the liver tissues was performed using RNA sequencing (RNA-seq). Our RNA-seq data revealed 692 differentially expressed genes involved in processes of lipid metabolism, oxidative stress, immune responses, and cell proliferation. Notably, the gene encoding neutral sphingomyelinase, SMPD3, was predominantly upregulated in the liver tissues of the mice displaying a phenotype of steatosis. Moreover, nSMase2 activity was elevated in these tissues of the liver. Pharmacological and genetic inhibition of nSMase2 prevented intracellular lipid accumulation and TNFα-induced inflammation in in-vitro HepG2-steatosis cellular model. Furthermore, nSMase2 inhibition ameliorates oxidative damage by rescuing PPARα and preventing cell death associated with high glucose/oleic acid-induced fat accumulation in HepG2 cells. Collectively, our findings highlight the prominent role of nSMase2 in hepatic steatosis, which could serve as a potential therapeutic target for NAFLD and other hepatic steatosis-linked disorders.

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“…BA metabolism is also altered in patients with hepatic steatosis and glucose and lipid dysmetabolism ( 136 ). Dysregulation of BA metabolism was linked to steatosis, inflammation, and fibrosis in patients with NAFLD ( 137 ). Intervention of BAs could effectively control and prevent obesity and NAFLD ( 132 , 138 ).…”

Section: Ba Metabolites and Immune-associated Disordersmentioning

confidence: 99%

Gut microbiota derived bile acid metabolites maintain the homeostasis of gut and systemic immunity

Gao

Yang

2023

Front. Immunol.

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Bile acids (BAs) as cholesterol-derived molecules play an essential role in some physiological processes such as nutrient absorption, glucose homeostasis and regulation of energy expenditure. They are synthesized in the liver as primary BAs such as cholic acid (CA), chenodeoxycholic acid (CDCA) and conjugated forms. A variety of secondary BAs such as deoxycholic acid (DCA) and lithocholic acid (LCA) and their derivatives is synthesized in the intestine through the involvement of various microorganisms. In addition to essential physiological functions, BAs and their metabolites are also involved in the differentiation and functions of innate and adaptive immune cells such as macrophages (Macs), dendritic cells (DCs), myeloid derived suppressive cells (MDSCs), regulatory T cells (Treg), Breg cells, T helper (Th)17 cells, CD4 Th1 and Th2 cells, CD8 cells, B cells and NKT cells. Dysregulation of the BAs and their metabolites also affects development of some diseases such as inflammatory bowel diseases. We here summarize recent advances in how BAs and their metabolites maintain gut and systemic homeostasis, including the metabolism of the BAs and their derivatives, the role of BAs and their metabolites in the differentiation and function of immune cells, and the effects of BAs and their metabolites on immune-associated disorders.

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Bile acids and sphingolipids in non-alcoholic fatty liver disease

Cited by 16 publications

References 74 publications

Diagnostic value of sphingolipid metabolism-related genes CD37 and CXCL9 in nonalcoholic fatty liver disease

Diagnostic value of sphingolipid metabolism-related genes CD37 and CXCL9 in nonalcoholic fatty liver disease

Neutral Sphingomyelinase 2 Inhibition Limits Hepatic Steatosis and Inflammation

Gut microbiota derived bile acid metabolites maintain the homeostasis of gut and systemic immunity

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