P465L‐PPARγ mutation confers partial resistance to the hypolipidaemic action of fibrates

Rodríguez‐Cuenca, Sergio; Carobbio, Stefania; Barceló‐Coblijn, Gwendolyn; Prieur, Xavier; Relat, Joana; Amat, Ramon; Campbell, Mark; Dias, Ana; Bahri, Myriam; Gray, Sarah L.; Vidal-Puig, António

doi:10.1111/dom.13370

Cited by 3 publications

(2 citation statements)

References 50 publications

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“…Real-Time PCR was performed in a 7900HT Fast Real-Time PCR System as described. 26 For all experiments, gene expression profiling was corrected by the geometric average of 18S, β2-microglobulin, β-actin, and 36B4. Heatmaps were generated using ClustVis (https://biit.cs.ut.ee/clust vis/).…”

Section: Real-time Pcrmentioning

confidence: 99%

Allostatic hypermetabolic response in PGC1α/β heterozygote mouse despite mitochondrial defects

et al. 2021

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Aging, obesity, and insulin resistance are associated with low levels of PGC1α and PGC1β coactivators and defective mitochondrial function. We studied mice deficient for PGC1α and PGC1β [double heterozygous (DH)] to investigate their combined pathogenic contribution. Contrary to our hypothesis, DH mice were leaner, had increased energy dissipation, a pro‐thermogenic profile in BAT and WAT, and improved carbohydrate metabolism compared to wild types. WAT showed upregulation of mitochondriogenesis/oxphos machinery upon allelic compensation of PGC1α4 from the remaining allele. However, DH mice had decreased mitochondrial OXPHOS and biogenesis transcriptomes in mitochondria‐rich organs. Despite being metabolically healthy, mitochondrial defects in DH mice impaired muscle fiber remodeling and caused qualitative changes in the hepatic lipidome. Our data evidence first the existence of organ‐specific compensatory allostatic mechanisms are robust enough to drive an unexpected phenotype. Second, optimization of adipose tissue bioenergetics is sufficient to maintain a healthy metabolic phenotype despite a broad severe mitochondrial dysfunction in other relevant metabolic organs. Third, the decrease in PGC1s in adipose tissue of obese and diabetic patients is in contrast with the robustness of the compensatory upregulation in the adipose of the DH mice.

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Section: Real-time Pcrmentioning

confidence: 99%

Allostatic hypermetabolic response in PGC1α/β heterozygote mouse despite mitochondrial defects

et al. 2021

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“…Fibrates increase the production of apolipoprotein AI (apoAI) and AII in the liver, which in turn stimulates HDL production. Triglyceride synthesis is also decreased and lipoprotein lipase activated in response to treatment with fibrates, reducing VLDL synthesis and enhancing its clearance [ 117 ]. In addition to fibrates, these approved drugs improve lipid metabolism, as shown in patients with dyslipidemia treated with bezafibrate [ 118 ], fenofibrate [ 119 ] and ciprofibrate [ 120 ] and to a lesser extent in patients treated with gemfibrozil [ 121 ].…”

Section: Ppar Ligand Therapeutics In Lipid Metabolism Disordermentioning

confidence: 99%

The Opportunities and Challenges of Peroxisome Proliferator-Activated Receptors Ligands in Clinical Drug Discovery and Development

Hong

Zhai

2018

IJMS

111

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Peroxisome proliferator-activated receptors (PPARs) are a well-known pharmacological target for the treatment of multiple diseases, including diabetes mellitus, dyslipidemia, cardiovascular diseases and even primary biliary cholangitis, gout, cancer, Alzheimer’s disease and ulcerative colitis. The three PPAR isoforms (α, β/δ and γ) have emerged as integrators of glucose and lipid metabolic signaling networks. Typically, PPARα is activated by fibrates, which are commonly used therapeutic agents in the treatment of dyslipidemia. The pharmacological activators of PPARγ include thiazolidinediones (TZDs), which are insulin sensitizers used in the treatment of type 2 diabetes mellitus (T2DM), despite some drawbacks. In this review, we summarize 84 types of PPAR synthetic ligands introduced to date for the treatment of metabolic and other diseases and provide a comprehensive analysis of the current applications and problems of these ligands in clinical drug discovery and development.

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When Adipose Tissue Lets You Down: Understanding the Functions of Genes Disrupted in Lipodystrophy

Rochford¹

2022

Diabetes

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Lipodystrophy syndromes are conditions in which the adipose tissue mass of an individual is altered inappropriately. The change in adipose mass can range from a relatively modest and subtle redistribution in some individuals with partial lipodystrophy to a near-complete absence of adipose tissue in the most severe forms of generalized lipodystrophy. The common feature is a disconnection between the need of the individual for a safe, healthy lipid storage capacity and the available adipose mass to perform this critical role. The inability to partition lipids for storage in appropriately functioning adipocytes leads to lipid accumulation in other tissues, which typically results in conditions such as diabetes, dyslipidemia, fatty liver, and cardiovascular disease. Several genes have been identified whose disruption leads to inherited forms of lipodystrophy. There is a link between some of these genes and adipose dysfunction, so the molecular basis of disease pathophysiology appears clear. However, for other lipodystrophy genes, it is not evident why their disruption should affect adipose development or function or, in the case of partial lipodystrophy, why only some adipose depots should be affected. Elucidating the molecular functions of these genes and their cellular and physiological effects has the capacity to uncover fundamental new insights regarding the development and functions of adipose tissue. This information is also likely to inform better management of lipodystrophy and improved treatments for patients. In addition, the findings will often be relevant to other conditions featuring adipose tissue dysfunction, including the more common metabolic disease associated with obesity.

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P465L‐PPARγ mutation confers partial resistance to the hypolipidaemic action of fibrates

Cited by 3 publications

References 50 publications

Allostatic hypermetabolic response in PGC1α/β heterozygote mouse despite mitochondrial defects

Allostatic hypermetabolic response in PGC1α/β heterozygote mouse despite mitochondrial defects

The Opportunities and Challenges of Peroxisome Proliferator-Activated Receptors Ligands in Clinical Drug Discovery and Development

When Adipose Tissue Lets You Down: Understanding the Functions of Genes Disrupted in Lipodystrophy

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