Hepatocyte-Secreted Autotaxin Exacerbates Nonalcoholic Fatty Liver Disease Through Autocrine Inhibition of the PPARα/FGF21 Axis

Han, Qi; Song, Erfei; Hu, Yue; Li, Tengfei; Ku, Kam Ching; Wang, Cunchuan; Cheung, Bernard M Y; Cheong, Lai Yee; Wang, Qin; Wu, Xiaoping; Hoo, Ruby L.C.; Wang, Yong; Xu, Aimin

doi:10.1016/j.jcmgh.2022.07.012

Cited by 13 publications

(8 citation statements)

References 81 publications

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“…Although the molecular mechanism remains unclear, the decreased levels of lysophosphatidic acid (LPA) and LPC by the deficiency of PLAAT1 were likely to be involved in the prevention of fatty liver since the inhibition of autotaxin, a secreted lysophospholipase D producing LPA from LPC, in HFD-fed mice was reported to increase the transcriptional activity of PPARα and hepatoprotective effects of FGF21, thereby suppressing HFD-induced increases in liver weight and TG levels. 47,48 Moreover, LPC was reported to function as a death effector in the lipoapoptosis of hepatocytes. 49 As a similar case with PLA 2 isoforms, the deficiency of calcium-independent PLA 2 β (iPLA 2 β) was reported to improve the obesity and hepatic steatosis in leptin-deficient mice, suggesting a deleterious role of this PLA 2 isoform in severe obesity-associated NAFLD.…”

Section: Discussionmentioning

confidence: 99%

“…These results suggested that PLAAT1 functions as PLA 1 /A 2 rather than N ‐acyltransferase in the liver. Although the molecular mechanism remains unclear, the decreased levels of lysophosphatidic acid (LPA) and LPC by the deficiency of PLAAT1 were likely to be involved in the prevention of fatty liver since the inhibition of autotaxin, a secreted lysophospholipase D producing LPA from LPC, in HFD‐fed mice was reported to increase the transcriptional activity of PPARα and hepatoprotective effects of FGF21, thereby suppressing HFD‐induced increases in liver weight and TG levels 47,48 . Moreover, LPC was reported to function as a death effector in the lipoapoptosis of hepatocytes 49 .…”

Section: Discussionmentioning

confidence: 99%

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PLAAT1 deficiency alleviates high‐fat diet‐induced hepatic lipid accumulation in mice

et al. 2023

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The phospholipase A and acyltransferase (PLAAT) family is composed of three isoforms in mice (PLAAT1, 3, and 5), all of which function as phospholipidmetabolizing enzymes exhibiting phospholipase A 1 /A 2 and acyltransferase activities. Plaat3-deficient (Plaat3 −/− ) mice were previously reported to show lean phenotype and remarkable hepatic fat accumulation under high-fat diet (HFD) feeding, while Plaat1 −/− mice have not been analyzed. In the present study, we generated Plaat1 −/− mice and investigated the effects of PLAAT1 deficiency on HFD-induced obesity, hepatic lipid accumulation, and insulin resistance. After HFD treatment, PLAAT1 deficiency caused a lower body weight gain compared to wild-type mice. Plaat1 −/− mice also showed reduced liver weight with negligible

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

PLAAT1 deficiency alleviates high‐fat diet‐induced hepatic lipid accumulation in mice

et al. 2023

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“…The expression and activity of SphK1 are significantly increased in fibrotic livers compared to normal livers, and SphK1 can promote liver fibrosis by modulating collagen deposition and α-SMA 223 . Notably, hepatocyte-secreted ATX can aggravate nonalcoholic fatty liver disease by autocrine inhibition of the PPARα/FGF21 axis 224 . On the other hand, inhibition of aSMase can prevent the progression of the early stage of nonalcoholic steatohepatitis 225 , collectively suggesting that sphingolipid-related enzymes can be therapeutic targets against metabolic disease.…”

Section: Disrupted Homeostasis Of Sphingolipids In Diseasementioning

confidence: 99%

Functional roles of sphingolipids in immunity and their implication in disease

Lee

Bae

2023

Exp Mol Med

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Sphingolipids, which are components of cellular membranes and organ tissues, can be synthesized or degraded to modulate cellular responses according to environmental cues, and the balance among the different sphingolipids is important for directing immune responses, regardless of whether they originate, as intra- or extracellular immune events. Recent progress in multiomics-based analyses and methodological approaches has revealed that human health and diseases are closely related to the homeostasis of sphingolipid metabolism, and disease-specific alterations in sphingolipids and related enzymes can be prognostic markers of human disease progression. Accumulating human clinical data from genome-wide association studies and preclinical data from disease models provide support for the notion that sphingolipids are the missing pieces that supplement our understanding of immune responses and diseases in which the functions of the involved proteins and nucleotides have been established. In this review, we analyze sphingolipid-related enzymes and reported human diseases to understand the important roles of sphingolipid metabolism. We discuss the defects and alterations in sphingolipid metabolism in human disease, along with functional roles in immune cells. We also introduce several methodological approaches and provide summaries of research on sphingolipid modulators in this review that should be helpful in studying the roles of sphingolipids in preclinical studies for the investigation of experimental and molecular medicines.

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“…The role of the intestinal microbiota in metabolic diseases has received increasing attention ( Wang et al, 2021 ). The imbalance of the microorganisms in the intestine is considered a contributing factor of NAFLD ( Qiu et al, 2022 ). The changes in peripheral and intrahepatic immune responses caused by ecological imbalance accelerate the development of NASH.…”

Section: Introductionmentioning

confidence: 99%

Effects of various interventions on non-alcoholic fatty liver disease (NAFLD): A systematic review and network meta-analysis

Wang

Jin²,

Li³

et al. 2023

Front. Pharmacol.

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Background: With the increasing prevalence of obesity and metabolic syndrome, the incidence of non-alcoholic fatty liver disease (NAFLD) is also increasing. In the next decade, NAFLD may become the main cause of liver transplantation. Therefore, the choice of treatment plan is particularly important. The purpose of this study was to compare several interventions in the treatment of NAFLD to provide some reference for clinicians in selecting treatment methods.Methods: We searched Public Medicine (PubMed), Medline, Excerpta Medica Database (Embase), and Cochrane Library from January 2013 to January 2023 to identify randomized controlled trials (RCTs) published in English. The network meta-analysis was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Forty-three studies accounting for a total of 2,969 patients were included, and alanine aminotransferase (ALT), total cholesterol (TC), and low-density lipoprotein cholesterol (LDL) were selected as outcome measures for analysis and comparison.Results: We evaluated the results of drug, diet, and lifestyle interventions between the intervention and control groups. Curcumin (CUN) and probiotics (PTC) were selected for medication, the Mediterranean diet (MDED) was selected for special diet (SPD), and various kinds of exercise and lifestyle advice were selected for lifestyle interventions (LFT). The SUCRA was used to rank interventions according to the effect on ALT indicators (SUCRA: PTC 80.3%, SPD 65.2%, LFT 61.4%, PLB 32.8%, CUN 10.2%), TC indicators (SUCRA: PTC 89.4%, SPD 64%, CUN 34%, LFT 36.6%, PLB 17%), and LDL indicators (SUCRA: PTC 84.2%, CUN 69.5%, LFT 51.7%, PLB 30.1%, SPD 14.5%). The pairwise meta-analysis results showed that MDED was significantly better than NT in improving ALT [SMD 1.99, 95% CI (0.38, 3.60)]. In terms of improving TC and LDL, ATS was significantly better than NT [SMD 0.19, 95% CI (0.03, 0.36)] [SMD 0.18, 95% CI (0.01, 0.35)].Conclusion: Our study showed that PTC is most likely to be the most effective treatment for improving NAFLD indicators. Professional advice on diet or exercise was more effective in treating NAFLD than no intervention.

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Hepatocyte-Secreted Autotaxin Exacerbates Nonalcoholic Fatty Liver Disease Through Autocrine Inhibition of the PPARα/FGF21 Axis

Cited by 13 publications

References 81 publications

PLAAT1 deficiency alleviates high‐fat diet‐induced hepatic lipid accumulation in mice

PLAAT1 deficiency alleviates high‐fat diet‐induced hepatic lipid accumulation in mice

Functional roles of sphingolipids in immunity and their implication in disease

Effects of various interventions on non-alcoholic fatty liver disease (NAFLD): A systematic review and network meta-analysis

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