The class 3 PI3K coordinates autophagy and mitochondrial lipid catabolism by controlling nuclear receptor PPARα

Abstract

The class 3 phosphoinositide 3-kinase (PI3K) is required for lysosomal degradation by autophagy and vesicular trafficking, assuring nutrient availability. Mitochondrial lipid catabolism is another energy source. Autophagy and mitochondrial metabolism are transcriptionally controlled by nutrient sensing nuclear receptors. However, the class 3 PI3K contribution to this regulation is unknown. We show that liver-specific inactivation of Vps15 , the essential regulatory subunit of the class 3 PI3K, elicits mitochondrial depletion and failure to oxidize fatty acids. Mechanistically, transcriptional activity of Peroxisome Proliferator Activated Receptor alpha (PPARα), a nuclear receptor orchestrating lipid catabolism, is blunted in Vps15 -deficient livers. We find PPARα repressors Histone Deacetylase 3 (Hdac3) and Nuclear receptor co-repressor 1 (NCoR1) accumulated in Vps15 -deficient livers due to defective autophagy. Activation of PPARα or inhibition of Hdac3 restored mitochondrial biogenesis and lipid oxidation in Vps15 -deficient hepatocytes. These findings reveal roles for the class 3 PI3K and autophagy in transcriptional coordination of mitochondrial metabolism.

Peroxisome Proliferator-Activated Receptors and Their Novel Ligands as Candidates for the Treatment of Non-Alcoholic Fatty Liver Disease

“…Lysosomal inhibition leads to downregulation of PPARα and its target genes, decreasing peroxisomal lipid oxidation and biogenesis [250]. The class 3 PI3K, Vps15, which plays a central role in autophagy, has been shown to control PPARα activation for lipid degradation and mitochondrial biogenesis [251]. In hepatocytes, PPARα activation promotes lipoprotein TG hydrolysis by increasing the enzyme activity of lipoprotein lipase (LPL) through a direct increase in its transcription, and decreases the expression of genes encoding lipoproteins, such as apolipoprotein C3 and apolipoprotein A4, which act as inhibitors of LPL activity [220,225].…”

Hepatic Lipid Catabolism via PPARα-Lysosomal Crosstalk

“…Thus, the loss of autophagy leads to an over-accumulation of NCoR1, which then suppresses PPARα activity and results in further impairment of autophagy and lipid oxidation [9] ( Figure 1B). Another study further supported the role of autophagy on PPARα action showing that hepatic expression of the class 3 PI3K is essential for metabolic adaptation to starvation in the liver through the control of PPARα transcriptional activity [59]. This study showed that the loss of hepatic expression of class 3 PI3K/Vps15 effected the levels of PPARα ligands, as well as PGC1α and NCoR1 levels [59].…”

“…However, in autophagy deficient Vps15-deficient hepatocytes this process is impaired, leading to NCoR1 stabilization and inhibition of hepatic PPARα activity. [59]. Therefore, the authors proposed that the class 3 PI3K/VPS15 exerted a broad transcriptional control in the liver to match autophagic activity with mitochondrial metabolism during fasting, via regulation of nuclear receptor action [59].…”

“…[59]. Therefore, the authors proposed that the class 3 PI3K/VPS15 exerted a broad transcriptional control in the liver to match autophagic activity with mitochondrial metabolism during fasting, via regulation of nuclear receptor action [59]. Additionally, several autophagy proteins themselves could also regulate NCoR1 corepressor activity by a non-autophagy-mediated mechanism to modify PPARα activity [60,61].…”

Puerarin Relieved Compression-Induced Apoptosis and Mitochondrial Dysfunction in Human Nucleus Pulposus Mesenchymal Stem Cells via the PI3K/Akt Pathway

“…PI3K/Akt deactivation was found to be also linked with mitochondria depolarization [53]. Mitochondrial biogenesis in hepatocytes required functional class 3 PI3K, which controls PPARα transcriptional activity and harmonizes energy demand with mitochondrial content [54]. Inhibition of PI3K was also found to disable the effect of PUR on mitochondrial homeostasis in nonalcoholic fatty liver disease [55].…”