FOXK1 promotes nonalcoholic fatty liver disease by mediating mTORC1-dependent inhibition of hepatic fatty acid oxidation

Fujinuma, Shun; Nakatsumi, Hirokazu; Shimizu, Hideyuki; Sugiyama, Shigeaki; Harada, Akihito; Goya, Tadanobu; Tanaka, Masanori; Kohjima, Motoyuki; Takahashi, Masatomo; Izumi, Yoshihiro; Yagi, Minoru; Kang, Dongchon; Kaneko, Mari; Shigeta, Mayo; Bamba, Takeshi; Ohkawa, Yasuyuki; Nakayama, Keiichi I.

doi:10.1016/j.celrep.2023.112530

Cited by 9 publications

(5 citation statements)

References 60 publications

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“…22 Additionally, FOXK1 has been implicated in nonalcoholic fatty liver disease and Parkinson's disease. 23,24 These studies indicate the participation of FOXK1 in various disease processes, including human cancers.…”

Section: Discussionmentioning

confidence: 88%

FOXK1 upregulation is correlated with tumor progression and tumor associated macrophages infiltration in renal cell carcinoma

Chen,

Pan,

Zhang

et al. 2023

Molecular Carcinogenesis

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Renal cell carcinoma (RCC) is one of the most common urological cancers in adults. Forkhead box k1 (FOXK1) is a transcription factor involved in the progression of various malignant tumors. In this study, we aimed to investigate the expression and roles of FOXK1 in RCC development. Our findings revealed increased expression of FOXK1 in RCC tumor tissues and cell lines compared with normal controls. Functional assays demonstrated that knockdown of FOXK1 significantly inhibited proliferation, migration, invasion, and promoted apoptosis in RCC cells. Furthermore, FOXK1 knockdown suppressed epithelial‐mesenchymal transition and Wnt signaling in RCC cells. Additionally, we observed a correlation between FOXK1 upregulation and tumor associated macrophages infiltration in RCC. These results suggest that FOXK1 acts as an oncogene in RCC and may serve as a potential therapeutic target for RCC treatment.

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Section: Discussionmentioning

confidence: 88%

FOXK1 upregulation is correlated with tumor progression and tumor associated macrophages infiltration in renal cell carcinoma

Chen,

Pan,

Zhang

et al. 2023

Molecular Carcinogenesis

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“…One candidate is FOXK1, which is dephosphorylated, and thereby activated, following mTORC1 activation in hepatocytes (He et al, 2018). Mice with hepatocyte-specific deletion of Foxk1 exhibit reduced lipogenic activities and increased catabolic activities, which are associated with protection from hepatic steatosis, inflammation, and fibrosis in the context of choline deficiency or diethylnitrosamine (DEN) coupled with HFD (Fujinuma et al, 2023).…”

Section: Discussionmentioning

confidence: 99%

p110α-dependent hepatocyte signaling is critical for liver gene expression and its rewiring in MASLD

Régnier,

Polizzi,

Fougeray

et al. 2024

Preprint

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Insulin and other growth factors are key regulators of liver gene expression, including in metabolic diseases. Most of the phosphoinositide 3-kinase (PI3K) activity induced by insulin is dependent on PI3Kα. We used mice lacking p110α, the catalytic subunit of PI3Kα, to investigate its role in the regulation of liver gene expression. The absence of hepatocyte PI3Kα signaling promoted glucose intolerance in lean mice and significantly regulated liver gene expression, including insulin-sensitive genes, inad libitumfeeding. Some of the defective regulation of gene expression in response to hepatocyte-restricted insulin receptor deletion was related to PI3Kα signaling. In addition, though PI3Kα deletion in hepatocytes promoted insulin resistance, it was protective against steatotic liver disease in diet-induced obesity. In the absence of hepatocyte PI3Kα, the effect of diet-induced obesity on liver gene expression was significantly altered, with changes in rhythmic gene expression in liver. Therefore, this study highlights the specific role of membrane signaling dependent on hepatocyte PI3Kα in the control of liver gene expression in physiology and in Metabolic dysfunction-Associated Steatotic Liver Disease (MASLD).HighlightsHepatocyte p110α is required for liver growth, glucose homeostasis, and regulation of liver gene expression.Hepatocyte p110α is dispensable for the regulation of carbohydrate sensing by ChREBP and fatty acid sensing by PPARα.Hepatocyte p110α-mediated regulation of gene expression is related to both insulin receptor-dependent and -independent pathways.Hepatocyte p110α is required for lipid homeostasis and the rewiring of gene expression that occurs during diet-induced obesity.

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“… 121 A recent study reported that FOXK1 suppressed mitochondrial fatty acid oxidation in an mTORC1-dependent manner during the pathogenesis of nonalcoholic fatty liver disease (NAFLD) to non-alcoholic steatohepatitis (NASH). 122 Additionally, mTORC1 is a regulator of mitochondrial dynamics and cell survival. A study revealed that the nutrient-sensing mTORC1 pathway facilitates DRP1’s pro-fission activity of mitochondria and apoptosis via promoting the translation of mitochondrial fission process 1 (MTFP).…”

Section: Mitochondrial As Signaling Hubs In Defining Cell Fatementioning

confidence: 99%

Mitochondrial dysfunction: mechanisms and advances in therapy

Zong,

Li,

Liao

et al. 2024

Sig Transduct Target Ther

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Mitochondria, with their intricate networks of functions and information processing, are pivotal in both health regulation and disease progression. Particularly, mitochondrial dysfunctions are identified in many common pathologies, including cardiovascular diseases, neurodegeneration, metabolic syndrome, and cancer. However, the multifaceted nature and elusive phenotypic threshold of mitochondrial dysfunction complicate our understanding of their contributions to diseases. Nonetheless, these complexities do not prevent mitochondria from being among the most important therapeutic targets. In recent years, strategies targeting mitochondrial dysfunction have continuously emerged and transitioned to clinical trials. Advanced intervention such as using healthy mitochondria to replenish or replace damaged mitochondria, has shown promise in preclinical trials of various diseases. Mitochondrial components, including mtDNA, mitochondria-located microRNA, and associated proteins can be potential therapeutic agents to augment mitochondrial function in immunometabolic diseases and tissue injuries. Here, we review current knowledge of mitochondrial pathophysiology in concrete examples of common diseases. We also summarize current strategies to treat mitochondrial dysfunction from the perspective of dietary supplements and targeted therapies, as well as the clinical translational situation of related pharmacology agents. Finally, this review discusses the innovations and potential applications of mitochondrial transplantation as an advanced and promising treatment.

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FOXK1 promotes nonalcoholic fatty liver disease by mediating mTORC1-dependent inhibition of hepatic fatty acid oxidation

Cited by 9 publications

References 60 publications

FOXK1 upregulation is correlated with tumor progression and tumor associated macrophages infiltration in renal cell carcinoma

FOXK1 upregulation is correlated with tumor progression and tumor associated macrophages infiltration in renal cell carcinoma

p110α-dependent hepatocyte signaling is critical for liver gene expression and its rewiring in MASLD

Mitochondrial dysfunction: mechanisms and advances in therapy

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