PPARɑ variant V227A reduces plasma triglycerides through enhanced lipoprotein lipolysis
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1216983 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR32169129_1.fastq.gz | Fastqsanger.gz | |||
| SRR32169129_2.fastq.gz | Fastqsanger.gz | |||
| SRR32169130_1.fastq.gz | Fastqsanger.gz | |||
| SRR32169130_2.fastq.gz | Fastqsanger.gz | |||
| SRR32169131_1.fastq.gz | Fastqsanger.gz |
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Project description:Human single nucleotide variants in peroxisome proliferator-activated receptor-ɑ (PPARɑ) have been associated with beneficial metabolic phenotypes yet their physiologic impact is unclear. Here, we developed a mouse model of a human PPARɑ variant encoding a substitution of valine for alanine at position 227 (V227A) to explore the role of this variant on systemic metabolism. While the variant did not alter body mass or liver lipid accumulation, this variant reduced plasma triglycerides, consistent with human cohort observations. Gene expression analysis revealed that the variant enhances Ppara target gene expression in the liver in a manner consistent with PPARɑ synthetic agonist treatment. The variant increased hepatic transcript expression of Lpl, the predominant enzyme responsible for circulating triglyceride hydrolysis. Further characterization revealed that heart tissue from variant mice exhibited increased Lpl expression and triglyceride hydrolysis activity, indicating that the heart serves as a major mediator of circulating triglyceride clearance. These findings validate human observational studies and clarify the physiological impact of this variant on plasma triglycerides.
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Project description:Background and Aims: Inflammasome-mediated caspase-1 activity regulates the maturation and release of the pro-inflammatory cytokines interleukin (IL)-1M-CM-^_ and IL-18. Recently, we showed that caspase-1 deficiency strongly reduces high fat diet-induced adiposity although the mechanism is still unclear. We now aimed to elucidate the mechanism by which caspase-1 deficiency reduces modulates resistance to high fat diet-feeding fat accumulation in adipose tissue by focusing on the role of caspase-1 in the regulation of triglyceride (TG)-rich lipoprotein metabolism. Methods: Caspase-1 deficient and wild-type mice (both C57Bl/6 background) were used to determine postprandial TG kinetics, intestinal TG absorption, VLDL-TG production as well as TG clearance, all of which strongly contribute to the supply of TG for storage in adipose tissue. Micro-array and qPCR analysis were used to unravel intestinal and hepatic metabolic pathways involved. Results: Caspase-1 deficiency reduced the postprandial response to an oral lipid load, while tissue specific clearance of TG-rich lipoproteins was not changed. Indeed, an oral olive oil gavage containing [3H]TG revealed that caspase-1 deficiency significantly decreased intestinal chylomicron-TG production and reduced the uptake of [3H]TG-derived FA by liver, muscle, and adipose tissue. Similarly, caspase-1 deficiency reduced the hepatic VLDL-TG production without reducing VLDL-apoB production, despite an elevated hepatic TG content. Pathway analysis revealed that caspase-1 deficiency reduces intestinal and hepatic expression of genes involved in lipogenesis. Conclusions: Absence of caspase-1 reduces assembly and secretion of TG-rich lipoproteins, thereby reducing the availability of TG-derived FA for uptake by peripheral organs including adipose tissue. We anticipate that caspase-1 represents a novel link between innate immunity and lipid metabolism. Keywords: Expression profiling by array Wild-type (WT) and Casp1-null mice were maintained at lab chow. Animals, aged between 14 and 16 weeks (n=3 per genotype), were killed and liver and intestinal segments were removed. Livers were isolated from mice that were fasted over night, whereas intesines were removed from mice 2 hrs after they received an oral lipid load.Total RNA was isolated and subjected to gene expression profiling.
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