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Citrate‐Dependent Activation of Acetyl CoA Carboxylase Promotes Renal Lipid Accumulation in a Rat Model of Chronic Kidney Disease.

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Title: Citrate‐Dependent Activation of Acetyl CoA Carboxylase Promotes Renal Lipid Accumulation in a Rat Model of Chronic Kidney Disease.
Authors: Sanz‐Gómez, Marta (AUTHOR), Linillos‐Pradillo, Beatriz (AUTHOR), Fernández de la Rosa, Rubén (AUTHOR), Aránguez, Isabel (AUTHOR), Kreutz, Reinhold (AUTHOR), García, Antonia (AUTHOR), Barbas, Coral (AUTHOR), Plaza, Adrián (AUTHOR), Fernández‐Alfonso, María S. (AUTHOR)
Source: Acta Physiologica. May2026, Vol. 242 Issue 5, p1-16. 16p.
Subjects: Acetyl-CoA carboxylase, Lipid metabolism, Citrates, Kidney injuries, Chronic kidney failure, Mitochondrial pathology, Metabolic regulation
Abstract: Background: Abnormal accumulation of lipids within the kidney contributes to the progression of chronic kidney disease, but the underlying metabolic mechanisms remain unclear. Citrate is a central metabolite in cellular energy regulation and is frequently elevated in advanced kidney disease, yet its impact on renal lipid metabolism has not been investigated. This study tested whether increased circulating citrate promotes lipid accumulation in the kidney by activating acetyl‐CoA carboxylase independently of adenosine monophosphate‐activated protein kinase. Methods: Male Munich Wistar Frömter rats, a genetic model of chronic kidney disease, were studied together with HEK293 cells exposed to citrate. Protein expression, phosphorylation, and polymerization were assessed using western blotting, q‐RT‐PCR, and native gel electrophoresis. Renal lipid composition was characterized by untargeted high‐performance liquid chromatography coupled with quadrupole time‐of‐flight mass spectrometry, and citrate levels were semi‐quantified using capillary electrophoresis–time‐of‐flight mass spectrometry. Results: MWF rats exhibited elevated plasma citrate, reduced vitamin D and bone mineral density, and increased renal fibrosis and mitochondrial dysfunction. Moreover, MWF showed higher expression of ATP‐citrate lyase and fatty acid synthase, together with reduced phosphorylation of acetyl‐CoA carboxylase and AMP‐activated protein kinase, increased renal lipid deposition, and elevated fatty acid content. In HEK293, citrate treatment reproduced these effects, inducing acetyl‐CoA carboxylase polymerization, lipid droplet formation, impaired mitochondrial activity, and increased superoxide production. Conclusion: This study identifies citrate‐dependent activation of acetyl‐CoA carboxylase as a driver of renal lipid accumulation and remodeling independently of AMP‐activated protein kinase, revealing a novel metabolic mechanism linking systemic citrate to kidney injury and potential therapeutic strategies. [ABSTRACT FROM AUTHOR]
Copyright of Acta Physiologica is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
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  Label: Title
  Group: Ti
  Data: Citrate‐Dependent Activation of Acetyl CoA Carboxylase Promotes Renal Lipid Accumulation in a Rat Model of Chronic Kidney Disease.
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  Data: <searchLink fieldCode="AR" term="%22Sanz‐Gómez%2C+Marta%22">Sanz‐Gómez, Marta</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Linillos‐Pradillo%2C+Beatriz%22">Linillos‐Pradillo, Beatriz</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Fernández+de+la+Rosa%2C+Rubén%22">Fernández de la Rosa, Rubén</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Aránguez%2C+Isabel%22">Aránguez, Isabel</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Kreutz%2C+Reinhold%22">Kreutz, Reinhold</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22García%2C+Antonia%22">García, Antonia</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Barbas%2C+Coral%22">Barbas, Coral</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Plaza%2C+Adrián%22">Plaza, Adrián</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Fernández‐Alfonso%2C+María+S%2E%22">Fernández‐Alfonso, María S.</searchLink> (AUTHOR)
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  Data: <searchLink fieldCode="JN" term="%22Acta+Physiologica%22">Acta Physiologica</searchLink>. May2026, Vol. 242 Issue 5, p1-16. 16p.
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  Data: <searchLink fieldCode="DE" term="%22Acetyl-CoA+carboxylase%22">Acetyl-CoA carboxylase</searchLink><br /><searchLink fieldCode="DE" term="%22Lipid+metabolism%22">Lipid metabolism</searchLink><br /><searchLink fieldCode="DE" term="%22Citrates%22">Citrates</searchLink><br /><searchLink fieldCode="DE" term="%22Kidney+injuries%22">Kidney injuries</searchLink><br /><searchLink fieldCode="DE" term="%22Chronic+kidney+failure%22">Chronic kidney failure</searchLink><br /><searchLink fieldCode="DE" term="%22Mitochondrial+pathology%22">Mitochondrial pathology</searchLink><br /><searchLink fieldCode="DE" term="%22Metabolic+regulation%22">Metabolic regulation</searchLink>
– Name: Abstract
  Label: Abstract
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  Data: Background: Abnormal accumulation of lipids within the kidney contributes to the progression of chronic kidney disease, but the underlying metabolic mechanisms remain unclear. Citrate is a central metabolite in cellular energy regulation and is frequently elevated in advanced kidney disease, yet its impact on renal lipid metabolism has not been investigated. This study tested whether increased circulating citrate promotes lipid accumulation in the kidney by activating acetyl‐CoA carboxylase independently of adenosine monophosphate‐activated protein kinase. Methods: Male Munich Wistar Frömter rats, a genetic model of chronic kidney disease, were studied together with HEK293 cells exposed to citrate. Protein expression, phosphorylation, and polymerization were assessed using western blotting, q‐RT‐PCR, and native gel electrophoresis. Renal lipid composition was characterized by untargeted high‐performance liquid chromatography coupled with quadrupole time‐of‐flight mass spectrometry, and citrate levels were semi‐quantified using capillary electrophoresis–time‐of‐flight mass spectrometry. Results: MWF rats exhibited elevated plasma citrate, reduced vitamin D and bone mineral density, and increased renal fibrosis and mitochondrial dysfunction. Moreover, MWF showed higher expression of ATP‐citrate lyase and fatty acid synthase, together with reduced phosphorylation of acetyl‐CoA carboxylase and AMP‐activated protein kinase, increased renal lipid deposition, and elevated fatty acid content. In HEK293, citrate treatment reproduced these effects, inducing acetyl‐CoA carboxylase polymerization, lipid droplet formation, impaired mitochondrial activity, and increased superoxide production. Conclusion: This study identifies citrate‐dependent activation of acetyl‐CoA carboxylase as a driver of renal lipid accumulation and remodeling independently of AMP‐activated protein kinase, revealing a novel metabolic mechanism linking systemic citrate to kidney injury and potential therapeutic strategies. [ABSTRACT FROM AUTHOR]
– Name: AbstractSuppliedCopyright
  Label:
  Group: Ab
  Data: <i>Copyright of Acta Physiologica is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract.</i> (Copyright applies to all Abstracts.)
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      – Type: doi
        Value: 10.1111/apha.70219
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      – Code: eng
        Text: English
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        PageCount: 16
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    Subjects:
      – SubjectFull: Acetyl-CoA carboxylase
        Type: general
      – SubjectFull: Lipid metabolism
        Type: general
      – SubjectFull: Citrates
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      – SubjectFull: Kidney injuries
        Type: general
      – SubjectFull: Chronic kidney failure
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      – SubjectFull: Mitochondrial pathology
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      – SubjectFull: Metabolic regulation
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      – TitleFull: Citrate‐Dependent Activation of Acetyl CoA Carboxylase Promotes Renal Lipid Accumulation in a Rat Model of Chronic Kidney Disease.
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              Text: May2026
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