Fructose-1,6-bisphosphatase is a nonenzymatic safety valve that curtails AKT activation to prevent insulin hyperresponsiveness

Gu, Leyi; Zhu, Yahui; Watari, Kosuke; Lee, Maiya; Liu, Junlai; Perez, Sofia; Thai, Melinda; Mayfield, Joshua E.; Zhang, Bichen; Rocha, Karina Cunha e; Li, Fuming; Kim, Laura C.; Jones, Alexander C.; Wierzbicki, Igor H.; Liu, Xiao; Newton, Alexandra C.; Kisseleva, Tatiana; Lee, Jun Hee; Ying, Wei; Gonzalez, David J.; Saltiel, Alan R.; Simon, M. Celeste; Karin, Michael

doi:10.1016/j.cmet.2023.03.021

Cited by 9 publications

(3 citation statements)

References 44 publications

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“…Cp LKO mice showed smaller amount of Tnfα in the liver, indicating a reduction in inflammatory infiltration ( Figure 2K and L ). Additionally, Cp LKO mice showed significantly lower levels of serum biomarkers for liver injury, such as alanine aminotransferase (ALT) and AST, and lower AST-to-ALT ratio ( Sorbi et al., 1999 ; Kew, 2000 ; Gu et al., 2023 ) compared to the control group ( Figure 2M–O ). Histological analysis of Masson and Sirius Red demonstrated that the hepatic fibrosis deposition was ameliorated in Cp KLO mice ( Figure 2P–R ).…”

Section: Resultsmentioning

confidence: 99%

Targeting hepatic ceruloplasmin mitigates nonalcoholic steatohepatitis by modulating bile acid metabolism

Jiang,

Wang,

et al. 2023

Journal of Molecular Cell Biology

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Non-alcoholic steatohepatitis (NASH) is a condition that progresses from non-alcoholic fatty liver disease (NAFLD) and is characterized by hepatic fat accumulation, inflammation, and fibrosis. It has the potential to lead to cirrhosis and liver cancer, with currently no effective pharmacological treatment available. In this study, we investigate the therapeutic potential of targeting ceruloplasmin (Cp), a copper-containing protein predominantly secreted by hepatocytes, for treating NASH. Our result show that hepatic Cp was remarkedly upregulated in individuals with NASH and the mouse NASH model. Hepatocyte-specific Cp ablation effectively attenuates the onset of dietary-induced NASH by decreasing lipid accumulation, curbing inflammation, mitigating fibrosis and ameliorating liver damage. By employing transcriptomics and metabolomics approaches, we have discovered that hepatic deletion of Cp brings about the remarkable restoration of NASH by profoundly influencing bile acid metabolism. Hepatic deletion of Cp effectively remodels bile acid metabolism by upregulating Cyp7a1 and Cyp8b1, which subsequently leads to enhanced bile acid synthesis and notable alterations in bile acid profiles. In conclusion, our studies elucidate the crucial involvement of Cp in NASH, highlighting its significance as a promising therapeutic target for the treatment of this disease.

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Section: Resultsmentioning

confidence: 99%

Targeting hepatic ceruloplasmin mitigates nonalcoholic steatohepatitis by modulating bile acid metabolism

Jiang,

Wang,

et al. 2023

Journal of Molecular Cell Biology

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“…FBP1 is increasingly identified as a tumor suppressor as loss of FBP1 expression has been shown to promote tumor progression by enhancing aerobic glycolysis, thereby resulting in poor prognosis in patients with clear cell renal cell carcinoma, breast cancer and hepatocellular carcinoma [13][14][15][16]. FBP1 also plays important role in pathophysiology of diabetes, obesity and insulin hyperresponsiveness [17][18][19][20]. However, to our knowledge, the role of FBP1 in epidermal homeostasis and psoriasis has not been studied.…”

Section: Introductionmentioning

confidence: 99%

FBP1 orchestrates keratinocyte proliferation/differentiation and suppresses psoriasis through metabolic control of histone acetylation

Zhang,

Yang,

Liu

et al. 2024

Cell Death Dis

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Keratinocyte proliferation and differentiation in epidermis are well-controlled and essential for reacting to stimuli such as ultraviolet light. Imbalance between proliferation and differentiation is a characteristic feature of major human skin diseases such as psoriasis and squamous cell carcinoma. However, the effect of keratinocyte metabolism on proliferation and differentiation remains largely elusive. We show here that the gluconeogenic enzyme fructose-1,6-bisphosphatase 1 (FBP1) promotes differentiation while inhibits proliferation of keratinocyte and suppresses psoriasis development. FBP1 is identified among the most upregulated genes induced by UVB using transcriptome sequencing and is elevated especially in upper epidermis. Fbp1 heterozygous mice exhibit aberrant epidermis phenotypes with local hyperplasia and dedifferentiation. Loss of FBP1 promotes proliferation and inhibits differentiation of keratinocytes in vitro. Mechanistically, FBP1 loss facilitates glycolysis-mediated acetyl-CoA production, which increases histone H3 acetylation at lysine 9, resulting in enhanced transcription of proliferation genes. We further find that the expression of FBP1 is dramatically reduced in human psoriatic lesions and in skin of mouse imiquimod psoriasis model. Fbp1 deficiency in mice facilitates psoriasis-like skin lesions development through glycolysis and acetyl-CoA production. Collectively, our findings reveal a previously unrecognized role of FBP1 in epidermal homeostasis and provide evidence for FBP1 as a metabolic psoriasis suppressor.

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“…FBP1 is increasingly identi ed as a tumor suppressor as loss of FBP1 expression has been shown to promote tumor progression by enhancing aerobic glycolysis, thereby resulting in poor prognosis in patients with clear cell renal cell carcinoma, breast cancer and hepatocellular carcinoma 13,14,15,16 . FBP1 also plays important role in pathophysiology of diabetes, obesity and insulin hyperresponsiveness 17,18,19,20 . However, to our knowledge, the role of FBP1 in epidermal homeostasis and psoriasis has not been studied.…”

Section: Introductionmentioning

confidence: 99%

FBP1 orchestrates keratinocyte proliferation/differentiation and suppresses psoriasis through metabolic control of histone acetylation

Gao,

Zhou,

Zhang

et al. 2023

Preprint

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Keratinocyte proliferation and differentiation in epidermis are well controlled and essential for reacting to stimuli such as ultraviolet light. Imbalance between proliferation and differentiation is a characteristic feature of major human skin diseases such as psoriasis and squamous cell carcinoma. However, the effect of keratinocyte metabolism on proliferation and differentiation remains largely elusive. We show here that the gluconeogenic enzyme fructose 1, 6-bisphosphatase 1 (FBP1) promotes differentiation while inhibits proliferation of keratinocyte and suppresses psoriasis development. FBP1 is identified among the most upregulated genes induced by UVB using transcriptome sequencing and is elevated especially in upper epidermis. FBP1 heterozygous mice exhibit aberrant epidermis phenotypes with local hyperplasia and dedifferentiation. Loss of FBP1 promotes proliferation and inhibits differentiation of keratinocytes in vitro. Mechanistically, FBP1 loss facilitates glycolysis-mediated acetyl-CoA production, which increases histone H3 acetylation at lysine 9, resulting in enhanced transcription of proliferation genes. We further find that the expression of FBP1 is dramatically reduced in human psoriatic lesions and in skin of mouse imiquimod psoriasis model. FBP1 deficiency in mice facilitates psoriasis development through glycolysis and acetyl-CoA production. Collectively, our findings reveal a previously unrecognized role of FBP1 in epidermal homeostasis and provide evidence for FBP1 as a metabolic psoriasis suppressor.

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Fructose-1,6-bisphosphatase is a nonenzymatic safety valve that curtails AKT activation to prevent insulin hyperresponsiveness

Cited by 9 publications

References 44 publications

Targeting hepatic ceruloplasmin mitigates nonalcoholic steatohepatitis by modulating bile acid metabolism

Targeting hepatic ceruloplasmin mitigates nonalcoholic steatohepatitis by modulating bile acid metabolism

FBP1 orchestrates keratinocyte proliferation/differentiation and suppresses psoriasis through metabolic control of histone acetylation

FBP1 orchestrates keratinocyte proliferation/differentiation and suppresses psoriasis through metabolic control of histone acetylation

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