Hepatic COX1 loss leads to impaired autophagic flux and exacerbates nonalcoholic steatohepatitis

Yu, Qian; Li, Chang; Niu, Qinghui; Wang, Jigang; Che, Zhaodi; Lei, Ke; Ren, He; Ma, Boyi; Ren, Yixing; Luo, Pingping; Fan, Zhuming; Zhang, Huan; Liu, Zhaohui; Tipoe, George L.; Xiao, Jia

doi:10.1016/j.apsb.2023.03.008

Cited by 5 publications

(3 citation statements)

References 80 publications

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“…238,239 As a result, the specific depletion of COX-1 in hepatocytes exacerbates NASH progression by impairing autophagic flux. 98 Intriguingly, whereas COX-1 and COX-2 usually showed similar enzymatic function in AA pathway activity, COX-2 does not participate in the protective capacity of COX-1 in NASH-related autophagic flux.…”

Section: Cox Members and Metabolites In Nafldmentioning

confidence: 98%

“…The expression levels of both COX-1 and COX-2 are notably elevated in fatty livers obtained from patients with NASH and diet-induced mouse NASH models. 98,101 The downstream TXA2 level and TXA receptor expression are consistently increased in fatty livers, and the activation of TXA2-TBXA2R facilitates NAFLD progression by activating the Ca 2+ -CaMKIIγ-PERK-C/ EBP-TRB3 axis in hepatocytes. 238,239 As a result, the specific depletion of COX-1 in hepatocytes exacerbates NASH progression by impairing autophagic flux.…”

Section: Cox Members and Metabolites In Nafldmentioning

confidence: 99%

“…COX-1 and COX-2 play pivotal roles in the initial step of prostanoid biosynthesis and are implicated in essential homeostatic processes, particularly in the context of inflammation. 237 In a recent report from Yu et al, 98 COX-1 is essential for autophagic homeostasis in hepatocytes by interacting with WIPI2 (WD repeat domain, phosphoinositide interacting 2), a key factor critically for autophagosome maturation. The expression levels of both COX-1 and COX-2 are notably elevated in fatty livers obtained from patients with NASH and diet-induced mouse NASH models.…”

Section: Biological Functions and Molecular Mechanisms Of Aa Pathway ...mentioning

confidence: 99%

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Emerging Roles and Therapeutic Applications of Arachidonic Acid Pathways in Cardiometabolic Diseases

Hu,

Li,

Cheng

et al. 2024

Circulation Research

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Cardiometabolic disease has become a major health burden worldwide, with sharply increasing prevalence but highly limited therapeutic interventions. Emerging evidence has revealed that arachidonic acid derivatives and pathway factors link metabolic disorders to cardiovascular risks and intimately participate in the progression and severity of cardiometabolic diseases. In this review, we systemically summarized and updated the biological functions of arachidonic acid pathways in cardiometabolic diseases, mainly focusing on heart failure, hypertension, atherosclerosis, nonalcoholic fatty liver disease, obesity, and diabetes. We further discussed the cellular and molecular mechanisms of arachidonic acid pathway–mediated regulation of cardiometabolic diseases and highlighted the emerging clinical advances to improve these pathological conditions by targeting arachidonic acid metabolites and pathway factors.

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Section: Cox Members and Metabolites In Nafldmentioning

confidence: 98%

Section: Cox Members and Metabolites In Nafldmentioning

confidence: 99%

Section: Biological Functions and Molecular Mechanisms Of Aa Pathway ...mentioning

confidence: 99%

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Emerging Roles and Therapeutic Applications of Arachidonic Acid Pathways in Cardiometabolic Diseases

Hu,

Li,

Cheng

et al. 2024

Circulation Research

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Gut microbiota of miR‐30a‐5p‐deleted mice aggravate high‐fat diet‐induced hepatic steatosis by regulating arachidonic acid metabolic pathway

Wang,

Zhang,

Wang

et al. 2024

Clinical & Translational Med

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BackgroundPatients with non‐alcoholic fatty liver disease (NAFLD) often exhibit hepatic steatosis and dyslipidemia. Studies have shown that intestinal microorganisms are closely related to the occurrence of NAFLD and atherosclerosis. Our previous study has underscored the protective role of microRNA‐30a‐5p (miR‐30a‐5p) against atherosclerosis.Methods and ResultsIn the present study, we aimed to elucidate the effect and underlying mechanism of the intestinal microorganisms of miR‐30a‐5p knockout (KO) mice on NAFLD. Our findings demonstrated that KO exacerbated high‐fat diet (HFD)‐induced hepatic steatosis and disrupted liver function, as evidenced by elevated levels of total cholesterol, low‐density lipoprotein, alanine aminotransferase, aspartate transaminase, and total bile acids in serum. Fecal microbiota from HFD‐fed KO mice induced hepatic steatosis, dyslipidemia, and higher levels of enzymes indicative of liver damage in wild‐type mice. Remarkably, KO mice significantly intensified the above effects. 16s rDNA sequencing and metabolomics of the intestinal microbiota in the HFD‐treated KO and WT mice showed that the loss of miR‐30a‐5p resulted in intestinal microbiota imbalance and was highly related to the arachidonic acid metabolic pathway. Targeted metabolomic in the liver tissues unveiled upregulation of COX‐related (PGF2a, 8‐iso‐PGF2a and PGF2) and LOX‐related (LTB4, LTD4, 12S‐HETE and 15S‐HETE) factors in HFD‐treated KO mice. Immunohistochemistry and transcriptional analyses showed that miR‐30a‐5p affected arachidonic acid metabolism through the LOX/COX pathways. Besides, COX/LOX pathways and hepatic steatosis were reversed after reintroducing miR‐30a‐5p in HFD‐treated KO mice.ConclusionsThis study reveals the pivotal mechanism by which miR‐30a‐5p and intestinal microbes regulate hepatic steatosis and abnormal lipid metabolism, offering promising avenues for NAFLD and atherosclerosis therapeutics.HighlightsMiR‐30a‐5p deletion aggravated hepatic steatosis and lipid disorder induced by an HFD in mice. Gut microbiota participated in the regulation of hepatic steatosis in the context of miR‐30a‐5p. Gut microbiota metabolism‐related arachidonic acid metabolic pathway contributed to miR‐30a‐5p‐regulated hepatic steatosis and lipid disorder. Reintroducing miR‐30a‐5p reversed hepatic steatosis and arachidonic acid metabolism disorder caused by HFD and miR‐30a‐5p deletion.

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Heme oxygenase 1-mediated ferroptosis in Kupffer cells initiates liver injury during heat stroke

Li,

Wei,

Liu

et al. 2024

Acta Pharmaceutica Sinica B

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Hepatic COX1 loss leads to impaired autophagic flux and exacerbates nonalcoholic steatohepatitis

Cited by 5 publications

References 80 publications

Emerging Roles and Therapeutic Applications of Arachidonic Acid Pathways in Cardiometabolic Diseases

Emerging Roles and Therapeutic Applications of Arachidonic Acid Pathways in Cardiometabolic Diseases

Gut microbiota of miR‐30a‐5p‐deleted mice aggravate high‐fat diet‐induced hepatic steatosis by regulating arachidonic acid metabolic pathway

Heme oxygenase 1-mediated ferroptosis in Kupffer cells initiates liver injury during heat stroke

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