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Aims/hypothesis <p><i>CIDEB</i> (cell death-inducing DFF45-like effector B) deficiency is associated with a reduced incidence of metabolic dysfunction-associated steatotic liver disease (MASLD) in humans; however, the underlying mechanism responsible for this protective effect remains unclear.</p> Methods <p>C57BL/6J male mice were fed a high-fat diet (HFD) to recapitulate key aspects of MASLD and hepatic insulin resistance. <i>Cideb</i> knockdown (KD) was achieved using a 2′-O-methoxyethyl (MOE) antisense oligonucleotide (ASO). In vivo rates of hepatic mitochondrial gluconeogenesis and tricarboxylic acid (TCA) cycle flux were assessed by Q-Flux. The Comprehensive Lab Animal Monitoring System (CLAMS) was used to evaluate rates of whole-body energy expenditure. Hepatic and peripheric insulin sensitivity were evaluated using hyperinsulinaemic–euglycaemic clamp studies combined with radio-labelled isotopes.</p> Results <p>We showed that <i>Cideb</i> ASO treatment increased rates of whole-body energy expenditure by ~25% and decreased hepatic triacylglycerol by ~65% in a HFD mouse model of MASLD compared with the wild-type mice. <i>Cideb</i> KD reduced hepatic fat content, which could mostly be attributed to increased rates of hepatic mitochondrial oxidation, in combination with reduced hepatic lipogenesis. Additionally, <i>Cideb</i> KD ameliorated HFD-induced insulin resistance, which could be attributed to decreased plasma membrane <i>sn</i>-1,2-diacylglycerols (DAGs)–protein kinase C (PKC)ε–insulin receptor kinase (IRK)<sup>T1150</sup> phosphorylation in liver and skeletal muscle.</p> Conclusions/interpretation <p>These findings demonstrate that <i>Cideb</i> KD enhances mitochondrial fat oxidation and reduces hepatic lipogenesis, which in turn mitigates HFD-induced hepatic steatosis and insulin resistance via the plasma membrane <i>sn</i>-1,2-DAGs–PKCε–IRK<sup>T1150</sup> pathway, highlighting its potential as a novel therapeutic approach for MASLD and type 2 diabetes.</p> Graphical Abstract <p></p>

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Cideb knockdown in mice increases mitochondrial fat oxidation and reverses hepatic steatosis and insulin resistance by the plasma membrane sn-1,2-DAGs–PKCε–insulin receptor kinaseT1150 pathway

  • 期刊论文

  • 发表日期：

    2025年9月4日

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  • Jie Zheng,
  • Rafael C. Gaspar,
  • Ikki Sakuma,
  • Brandon T. Hubbard,
  • Dongyan Zhang,
  • Ali Nasiri,
  • Mario Kahn,
  • Mark Perelis,
  • Varman T. Samuel,
  • Kitt F. Petersen,
  • Gerald I. Shulman

摘要

Aims/hypothesis

CIDEB (cell death-inducing DFF45-like effector B) deficiency is associated with a reduced incidence of metabolic dysfunction-associated steatotic liver disease (MASLD) in humans; however, the underlying mechanism responsible for this protective effect remains unclear.

Methods

C57BL/6J male mice were fed a high-fat diet (HFD) to recapitulate key aspects of MASLD and hepatic insulin resistance. Cideb knockdown (KD) was achieved using a 2′-O-methoxyethyl (MOE) antisense oligonucleotide (ASO). In vivo rates of hepatic mitochondrial gluconeogenesis and tricarboxylic acid (TCA) cycle flux were assessed by Q-Flux. The Comprehensive Lab Animal Monitoring System (CLAMS) was used to evaluate rates of whole-body energy expenditure. Hepatic and peripheric insulin sensitivity were evaluated using hyperinsulinaemic–euglycaemic clamp studies combined with radio-labelled isotopes.

Results

We showed that Cideb ASO treatment increased rates of whole-body energy expenditure by ~25% and decreased hepatic triacylglycerol by ~65% in a HFD mouse model of MASLD compared with the wild-type mice. Cideb KD reduced hepatic fat content, which could mostly be attributed to increased rates of hepatic mitochondrial oxidation, in combination with reduced hepatic lipogenesis. Additionally, Cideb KD ameliorated HFD-induced insulin resistance, which could be attributed to decreased plasma membrane sn-1,2-diacylglycerols (DAGs)–protein kinase C (PKC)ε–insulin receptor kinase (IRK)T1150 phosphorylation in liver and skeletal muscle.

Conclusions/interpretation

These findings demonstrate that Cideb KD enhances mitochondrial fat oxidation and reduces hepatic lipogenesis, which in turn mitigates HFD-induced hepatic steatosis and insulin resistance via the plasma membrane sn-1,2-DAGs–PKCε–IRKT1150 pathway, highlighting its potential as a novel therapeutic approach for MASLD and type 2 diabetes.

Graphical Abstract