PPARs in liver physiology

Berthier, Alexandre; Johanns, Manuel; Zummo, Francesco Paolo; Lefèbvre, Philippe; Staels, Bart

doi:10.1016/j.bbadis.2021.166097

Cited by 55 publications

(38 citation statements)

References 167 publications

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“…Although PPARδ agonists have not yet been tested in outcome trials, all PPARs might affect CVD and heart failure through complex systemic actions that modulate cardiovascular risk factors and improve NASH, which is an increasing health problem and a cardiovascular risk factor 172 . Interestingly, several dual-PPAR and pan-PPAR agonists are being tested in clinical trials, currently mainly in patients with NAFLD 173 .…”

Section: Future Directionsmentioning

confidence: 99%

PPAR control of metabolism and cardiovascular functions

2021

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Peroxisome proliferator-activated receptor-α (PPARα), PPARδ and PPARγ are transcription factors that regulate gene expression following ligand activation. PPARα increases cellular fatty acid uptake, esterification and trafficking and regulates lipoprotein metabolism genes. PPARδ stimulates lipid and glucose utilization by increasing mitochondrial function and fatty acid desaturation pathways. By contrast, PPARγ promotes fatty acid uptake, triglyceride formation and storage in lipid droplets, thereby improving insulin sensitivity and glucose metabolism. PPARs also exert anti-atherogenic and anti-inflammatory effects on the vascular wall and immune cells. Clinically, PPARγ activation by glitazones and PPARα activation by fibrates improve insulin resistance and dyslipidaemia, respectively. PPARs are also physiological master switches in the heart, steering cardiac energy metabolism in cardiomyocytes, thereby affecting pathological heart failure and diabetic cardiomyopathy. Novel PPAR agonists in clinical development are providing new opportunities in the management of metabolic and cardiovascular diseases.

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Section: Future Directionsmentioning

confidence: 99%

PPAR control of metabolism and cardiovascular functions

2021

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“…Moreover, it has been shown that retinol promotes normal growth and development of the host ( 38 ). PPAR signaling pathway regulates the expression of genes associated with lipid metabolism, fat formation, maintenance of metabolic homeostasis, and inflammation ( 39 ). Therefore, GAT-2 might regulate excessive fat deposition and inflammation in the livers of female mice, whereas GAT-2 could affect normal growth and development of livers in male mice involving retinol metabolism and PPAR signaling pathway.…”

Section: Discussionmentioning

confidence: 99%

Transcriptomic Analysis Reveals a Sex-Dimorphic Influence of GAT-2 on Murine Liver Function

Zhang

et al. 2021

Front. Nutr.

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Accumulating evidence shows that the γ-amino butyric acid (GABA)ergic system affects the functions of different organs, and liver is one of the most sex-dimorphic organs in animals. However, whether and how the GABAergic system influences liver function in a sex-specific manner at the intrinsic molecular level remains elusive. In this study, firstly, we find that the levels of GABA are significantly increased in the livers of female mice with GABA transporter (GAT)-2 deficiency (KO) whereas it only slightly increased in male GAT-2 KO mice. Apart from the amino acid profiles, the expressions of toll-like receptors (TLRs) also differ in the livers of female and male KO mice. Moreover, RNA-seq results show 2,227 differentially expressed genes (DEGs) in which 1,030 are upregulated whereas 1,197 that are downregulated in the livers of female KO mice. Notably, oxidative phosphorylation, non-alcoholic fatty liver disease, Huntington's disease, and peroxisome proliferator-activated receptor (PPAR) signaling pathways are highly enriched by GAT-2 deficiency, indicating that these pathways probably meditate the effects of GAT-2 on female liver functions, on the other hand, only 1,233 DEGs, including 474 are upregulated and 759 are downregulated in the livers of male KO mice. Interestingly, retinol metabolism, PPAR signaling pathway, and tuberculosis pathways are substantially enriched by GAT-2 deficiency, suggesting that these pathways may be responsible for the effects of GAT-2 on male liver functions. Collectively, our results reveal the sex-dimorphic effects of GAT-2 in guiding liver functions, and we propose that targeting the GABAergic system (e.g., GATs) in a sex-specific manner could provide previously unidentified therapeutic opportunities for liver diseases.

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“…Peroxisome proliferator-activated receptors (PPARs) alpha (PPARα, Chr 22) and gamma (PPARγ, Chr 3) are ligand-activated transcription factors of the nuclear receptor superfamily. PPARs are activated by unsaturated fatty acids and form heterodimers with retinoid X receptors (RXRs) to regulate the peroxisomal beta-oxidation of fatty acids [ 108 ]. PPARα promotes fatty acid oxidation, and PPARγ increases lipogenesis and adipogenesis.…”

Section: Genetics Of Ldl Cholesterol In the Big-data Eramentioning

confidence: 99%

Genetic Determinants of Plasma Low-Density Lipoprotein Cholesterol Levels: Monogenicity, Polygenicity, and “Missing” Heritability

Martín‐Campos

2021

Biomedicines

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Changes in plasma low-density lipoprotein cholesterol (LDL-c) levels relate to a high risk of developing some common and complex diseases. LDL-c, as a quantitative trait, is multifactorial and depends on both genetic and environmental factors. In the pregenomic age, targeted genes were used to detect genetic factors in both hyper- and hypolipidemias, but this approach only explained extreme cases in the population distribution. Subsequently, the genetic basis of the less severe and most common dyslipidemias remained unknown. In the genomic age, performing whole-exome sequencing in families with extreme plasma LDL-c values identified some new candidate genes, but it is unlikely that such genes can explain the majority of inexplicable cases. Genome-wide association studies (GWASs) have identified several single-nucleotide variants (SNVs) associated with plasma LDL-c, introducing the idea of a polygenic origin. Polygenic risk scores (PRSs), including LDL-c-raising alleles, were developed to measure the contribution of the accumulation of small-effect variants to plasma LDL-c. This paper discusses other possibilities for unexplained dyslipidemias associated with LDL-c, such as mosaicism, maternal effect, and induced epigenetic changes. Future studies should consider gene–gene and gene–environment interactions and the development of integrated information about disease-driving networks, including phenotypes, genotypes, transcription, proteins, metabolites, and epigenetics.

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PPARs in liver physiology

Cited by 55 publications

References 167 publications

PPAR control of metabolism and cardiovascular functions

PPAR control of metabolism and cardiovascular functions

Transcriptomic Analysis Reveals a Sex-Dimorphic Influence of GAT-2 on Murine Liver Function

Genetic Determinants of Plasma Low-Density Lipoprotein Cholesterol Levels: Monogenicity, Polygenicity, and “Missing” Heritability

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