Multiple omics study identifies an interspecies conserved driver for nonalcoholic steatohepatitis

Zhang, Xiaojing; She, Zhi‐Gang; Wang, Junyong; Sun, Dating; Shen, Lijun; Xiang, Hui; Xu, Cheng; Ji, Yan‐Xiao; Huang, Yaji; Li, Penglong; Yang, Xia; Cheng, Yun; Ma, Junpeng; Wang, Haiping; Hu, Yufeng; Hu, Fengjiao; Shen, Tian; Tian, Han; Zhang, Peng; Zhao, Guang‐Nian; Wang, Lin; Hu, Manli; Yang, Qin; Zhu, Lihua; Cai, Jingjing; Yang, Juan; Zhang, Xin; Ma, Xin‐Liang; Xu, Qingbo; Touyz, Rhian M.; Loomba, Rohit; Wang, Yibin; Li, Hongliang

doi:10.1126/scitranslmed.abg8117

Cited by 27 publications

(27 citation statements)

References 74 publications

(85 reference statements)

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“…3B and fig. S3, A and B), consistent with our observations in Alox12 -knockout (KO) animals ( 9 ). However, in cultured hepatocytes, ML355 treatment had a negligible influence on lipid accumulation, fatty acid β-oxidation, ACC1 expression, and protein malonylation (Fig.…”

Section: Resultssupporting

confidence: 90%

“…We identified ALOX12 as a key regulator of lipotoxicity-derived NASH progression ( 9 ), raising the prospect of ALOX12-targeted therapy for the disease. In the current study, we further evaluated whether pharmacological inhibition of ALOX12 is an effective approach for the treatment of NASH.…”

Section: Resultsmentioning

confidence: 99%

“…Here, we introduce a treatment for NASH in both rodents and nonhuman primates involving targeted interruption of the ALOX12-ACC1 interaction using the small-molecule IMA-1. We established that ALOX12 is a key regulator of lipotoxicity-mediated NASH progression ( 9 ). However, unlike conventional ALOX12 inhibitors that target the lipoxygenase activity of ALOX12 ( 16 , 36 , 37 ), IMA-1 has a negligible impact on the catalytic activity of ALOX12 in the production of 12-HETE.…”

Section: Discussionmentioning

confidence: 99%

“…On the basis of multiomics studies and multilayered validations across species, we established that the arachidonate 12-lipoxygenase (ALOX12)–acetyl–coenzyme A (CoA) carboxylase 1 (ACC1) axis functions as a central driver of NASH progression ( 9 ). Previous studies from our group and others have demonstrated the involvement of ALOX12 in liver injuries such as hepatic ischemia reperfusion injury and Ccl4-triggered liver damage ( 10 – 12 ).…”

Section: Introductionmentioning

confidence: 99%

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A small molecule targeting ALOX12-ACC1 ameliorates nonalcoholic steatohepatitis in mice and macaques

Zhang

et al. 2021

Sci. Transl. Med.

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Section: Resultssupporting

confidence: 90%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

A small molecule targeting ALOX12-ACC1 ameliorates nonalcoholic steatohepatitis in mice and macaques

Zhang

et al. 2021

Sci. Transl. Med.

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“…Moreover, 12/15-lipoxygenase has been functionally connected to hydroperoxy-phosphatidylethanolamine-related ferroptosis [ 88 ]. Recently, arachidonate 12-lipoxygenase (ALOX-12) promotes the progression NASH via its interaction with acetyl-CoA carboxylase 1 (ACC1) [ 89 , 90 ]. However, whether ferroptosis plays a role in ALOX-12‒mediated NASH remains an open question.…”

Section: Introductionmentioning

confidence: 99%

The multifaceted role of ferroptosis in liver disease

et al. 2022

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Ferroptosis is an iron-dependent form of non-apoptotic cell death characterized by excessive lipid peroxidation and associated with a plethora of pathological conditions in the liver. Emerging evidence supports the notion that dysregulated metabolic pathways and impaired iron homeostasis play a role in the progression of liver disease via ferroptosis. Although the molecular mechanisms by which ferroptosis causes disease are poorly understood, several ferroptosis-associated genes and pathways have been implicated in liver disease. Here, we review the physiological role of the liver in processing nutrients, our current understanding of iron metabolism, the characteristics of ferroptosis, and the mechanisms that regulate ferroptosis. In addition, we summarize the role of ferroptosis in the pathogenesis of liver disease, including liver injury, non-alcoholic steatohepatitis, liver fibrosis, liver cirrhosis, and hepatocellular carcinoma. Finally, we discuss the therapeutic potential of targeting ferroptosis for managing liver disease.

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Targeting peroxisome proliferator‐activated receptor γ proteasomal degradation by magnolol is a potential avenue for adipogenesis‐mediated metabolic homeostasis

Mei

Wang

et al. 2023

Obesity

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Objective Adipogenesis has been recognized as an attractive avenue for maintaining systemic homeostasis, with peroxisome proliferator‐activated receptor γ (PPARγ) showing predominant roles in this process. This study aims to identify promising drug candidates by targeting PPARγ for adipogenesis‐based metabolic homeostasis and to clarify the detailed mechanisms. Methods Molecular events contributing to adipogenesis were screened, which identified PPARγ as having the predominant role. Promising agents of adipogenesis agonism were screened using a PPARγ‐based luciferase reporter assay. The functional capacity and molecular mechanisms of magnolol were intensively examined using 3T3‐L1 preadipocytes and dietary models. Results This study found that F‐box only protein 9 (FBXO9)‐mediated lysine 11 (K11)‐linked ubiquitination and proteasomal degradation of PPARγ are critically required during adipogenesis and systemic homeostasis. Notably, magnolol was identified as a potent adipogenesis activator by stabilizing PPARγ. The pharmacological mechanisms investigations clarified that magnolol directly binds to PPARγ and markedly interrupts its interaction with FBXO9, leading to a decline in K11‐linked ubiquitination and proteasomal degradation of PPARγ. Clinically important, magnolol treatment significantly facilitates adipogenesis in vitro and in vivo. Conclusions The downregulation of K11‐linked ubiquitination of PPARγ caused by FBOX9 is essentially required for adipogenesis, while targeting PPARγ‐FBXO9 interaction provides a new avenue for the therapy of adipogenesis‐related metabolic disorder.

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Multiple omics study identifies an interspecies conserved driver for nonalcoholic steatohepatitis

Abstract: ALOX12 drives NASH by inhibiting ACC1 lysosomal degradation across multiple species.

Cited by 27 publications

References 74 publications

A small molecule targeting ALOX12-ACC1 ameliorates nonalcoholic steatohepatitis in mice and macaques

A small molecule targeting ALOX12-ACC1 ameliorates nonalcoholic steatohepatitis in mice and macaques

The multifaceted role of ferroptosis in liver disease

Targeting peroxisome proliferator‐activated receptor γ proteasomal degradation by magnolol is a potential avenue for adipogenesis‐mediated metabolic homeostasis

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