Discordant hepatic fatty acid oxidation and triglyceride hydrolysis leads to liver disease

Selen, Ebru Selin; Choi, Joseph; Wolfgang, Michael J.

doi:10.1172/jci.insight.135626

Cited by 39 publications

(22 citation statements)

References 33 publications

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“…The increased expression of markers of gluconeogenesis observed in the present study is more likely due to increased mitochondrial metabolism, as previous studies demonstrate that induction of lipid oxidation is required for the endergonic steps of gluconeogenesis. In the case of an increased systemic energy demand, i.e., during exercise, both processes, fatty acid oxidation and gluconeogenesis, are constitutively activated [58,59].…”

Section: Discussionmentioning

confidence: 99%

Maternal Exercise Mediates Hepatic Metabolic Programming via Activation of AMPK-PGC1α Axis in the Offspring of Obese Mothers

Kasper

Breuer

Hoffmann

et al. 2021

Cells

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Maternal obesity is associated with an increased risk of hepatic metabolic dysfunction for both mother and offspring and targeted interventions to address this growing metabolic disease burden are urgently needed. This study investigates whether maternal exercise (ME) could reverse the detrimental effects of hepatic metabolic dysfunction in obese dams and their offspring while focusing on the AMP-activated protein kinase (AMPK), representing a key regulator of hepatic metabolism. In a mouse model of maternal western-style-diet (WSD)-induced obesity, we established an exercise intervention of voluntary wheel-running before and during pregnancy and analyzed its effects on hepatic energy metabolism during developmental organ programming. ME prevented WSD-induced hepatic steatosis in obese dams by alterations of key hepatic metabolic processes, including activation of hepatic ß-oxidation and inhibition of lipogenesis following increased AMPK and peroxisome-proliferator-activated-receptor-γ-coactivator-1α (PGC-1α)-signaling. Offspring of exercised dams exhibited a comparable hepatic metabolic signature to their mothers with increased AMPK-PGC1α-activity and beneficial changes in hepatic lipid metabolism and were protected from WSD-induced adipose tissue accumulation and hepatic steatosis in later life. In conclusion, this study demonstrates that ME provides a promising strategy to improve the metabolic health of both obese mothers and their offspring and highlights AMPK as a potential metabolic target for therapeutic interventions.

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Section: Discussionmentioning

confidence: 99%

Maternal Exercise Mediates Hepatic Metabolic Programming via Activation of AMPK-PGC1α Axis in the Offspring of Obese Mothers

Kasper

Breuer

Hoffmann

et al. 2021

Cells

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“…These findings indicate that adipocyte ATGL-dependent lipolysis is required for fasting-induced PPARα-dependent hepatic gene expression, and that together they orchestrate the fasting response in the liver. Interestingly, a recent study, using liver-specific deletion of Atgl in mice, has reported that hepatic ATGL is not required for the fasting-induced PPARα-dependent responses in the liver, suggesting that adipocyte lipolysis-derived fatty acids are sufficient to activate PPARα independent of the hepatocyte lipolysis [35].…”

Section: Discussionmentioning

confidence: 99%

ATGL-dependent white adipose tissue lipolysis controls hepatocyte PPARα activity

Fougerat

Schoiswohl

Polizzi

et al. 2021

Preprint

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ObjectiveIn hepatocytes, peroxisome proliferator-activated receptor α (PPARα) acts as a lipid sensor that regulates hepatic lipid catabolism during fasting and orchestrates a genomic response required for whole-body homeostasis. This includes the biosynthesis of ketone bodies and the secretion of the starvation hormone fibroblast growth factor 21 (FGF21). Several lines of evidence suggest that adipose tissue lipolysis contributes to this specific process. However, whether adipose tissue lipolysis is a dominant signal for the extensive remodeling of liver gene expression dependent on PPARα has not been investigated.MethodsFirst, using mice lacking adipose tissue lipolysis through adipocyte-specific deletion of adipose triglyceride lipase (ATGL), we characterized the responses dependent on adipocyte ATGL during fasting. Next, we performed liver whole genome expression analysis in fasted mice upon deletion of adipocyte ATGL or hepatocyte PPARα. Finally, we tested the consequences of hepatocyte-specific PPARα deficiency during pharmacological induction of adipocyte lipolysis with a β3-adrenergic receptor agonist.ResultsIn the absence of ATGL in adipocytes, ketone body and FGF21 productions were impaired in response to starvation. Liver transcriptome analysis revealed that adipocyte ATGL is critical for regulation of hepatic gene expression during fasting and highlighted a strong enrichment in PPARα target genes in this condition. Genome expression analysis confirmed that a large set of fasting-induced genes are sensitive to both ATGL and PPARα. Adipose tissue lipolysis induced by acute activation of the β3-adrenergic receptor also triggered PPARα-dependent responses in the liver, supporting a role for adipocyte-derived fatty acids as dominant signals for hepatocyte PPARα activity. In addition, the absence of hepatocyte PPARα altered brown adipose tissue (BAT) morphology and reduced UCP1 expression upon stimulation of the β3-adrenergic receptor. In agreement with this finding, mice lacking hepatocyte PPARα showed decreased tolerance to acute cold exposure.ConclusionsThese results underscore the central role of hepatocyte PPARα in the sensing of adipocyte-derived fatty acids and reveal that its activity is essential for full activation of BAT. Intact PPARα activity in hepatocytes is required for cross-talk between adipose tissues and the liver during fat mobilization during fasting and cold exposure.

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“…This ultimately requires tight coordination between the hepatocyte’s metabolic state, genome architecture, and transcriptional output. Fasting Cpt2 L−/− mice prompts accumulation of fatty acids, including putative endogenous Pparα ligands (Lee et al, 2016; Selen et al, 2021). Using this mouse genetic model and a combination of next-generation sequencing platforms we clarify the role for hepatic lipid content in metabolic gene transcription, and in particular how Pparα, activated by natural ligands, maintains the transcriptional architecture necessary for target gene expression ( Fig.…”

Section: Discussionmentioning

confidence: 99%

Pparα and fatty acid oxidation coordinate hepatic transcriptional architecture

Cavagnini

Wolfgang

2021

Preprint

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Fasting requires tight coordination between the metabolism and transcriptional output of hepatocytes to maintain systemic glucose and lipid homeostasis. Deficits in hepatic fatty acid oxidation result in dramatic fasting-induced hepatocyte lipid accumulation and induction of genes for oxidative metabolism that are largely driven by Pparα. While fatty acid oxidation is required for a rise in acetyl-CoA and subsequent lysine acetylation following a fast, changes in histone acetylation (total, H3K9ac, and H3K27ac) do not require fatty acid oxidation. Active enhancers in fasting mice are enriched for Pparα binding motifs. Genetically-defined inhibition of hepatic fatty acid oxidation results in higher levels of chromatin accessibility as well as elevated enhancer priming and acetylation proximal to Pparα sites largely associated with genes in lipid metabolism. Also, greater number of Pparα-associated H3K27ac signal changes occur at active enhancers compared to promoters, suggesting a mechanism for Pparα to tune target expression levels at pre-primed sites. Overall, these data show the requirement for Pparα activation in maintaining transcriptionally permissive hepatic genomic architecture particularly when fatty acid oxidation is limiting.HIGHLIGHTSFasting-induced transcription and histone acetylation are largely independent of acetyl-CoA concentration.Deficits in fatty acid oxidation prompt epigenetic changes and Pparα-sensitive transcription.Fasting prompts enhancer priming and acetylation proximal to Pparα binding sites independent of Pparα.Patterns of Pparα target genes can be distinguished by epigenetic marks at promoters and enhancers.

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Discordant hepatic fatty acid oxidation and triglyceride hydrolysis leads to liver disease

Cited by 39 publications

References 33 publications

Maternal Exercise Mediates Hepatic Metabolic Programming via Activation of AMPK-PGC1α Axis in the Offspring of Obese Mothers

Maternal Exercise Mediates Hepatic Metabolic Programming via Activation of AMPK-PGC1α Axis in the Offspring of Obese Mothers

ATGL-dependent white adipose tissue lipolysis controls hepatocyte PPARα activity

Pparα and fatty acid oxidation coordinate hepatic transcriptional architecture

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