Hepatic Lipid Catabolism via PPARα-Lysosomal Crosstalk - PubMed (original) (raw)

Review

Hepatic Lipid Catabolism via PPARα-Lysosomal Crosstalk

Rohit A Sinha et al. Int J Mol Sci. 2020.

Abstract

Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors which belong to the nuclear hormone receptor superfamily. They regulate key aspects of energy metabolism within cells. Recently, PPARα has been implicated in the regulation of autophagy-lysosomal function, which plays a key role in cellular energy metabolism. PPARα transcriptionally upregulates several genes involved in the autophagy-lysosomal degradative pathway that participates in lipolysis of triglycerides within the hepatocytes. Interestingly, a reciprocal regulation of PPARα nuclear action by autophagy-lysosomal activity also exists with implications in lipid metabolism. This review succinctly discusses the unique relationship between PPARα nuclear action and lysosomal activity and explores its impact on hepatic lipid homeostasis under pathological conditions such as non-alcoholic fatty liver disease (NAFLD).

Keywords: NAFLD; NCoR1; PGC1α; PPARs; autophagy; lipophagy; lysosomes; peroxisomes.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1

Figure 1

Reciprocal regulation of PPARα and autophagy-lysosomal signaling. (A) Induction of PPARα leads to increased transcription of autophagy (Atg) genes through either direct binding of PPARα to their promoter or through secondary regulation of TFEB levels. Induction of autophagy genes leads to engulfment of intrahepatic lipid droplets by autophagosomes and their eventual hydrolysis in lysosomal compartment termed as “lipophagy”. The free fatty acids released from lysosomes serve as substrate for mitochondrial β-oxidation further induced by PPARα leading to energy generation; (B) Impairment of autophagy-lysosomal activity leads to increased stability of PPARα corepressor NCoR1 as well as decreased stability of PPARα coactivator PGC1α leading to suppression of PPARα transactivation activity and reduced lipid catabolism in liver cells. The dotted up and down arrows denotes increase or decrease in levels.

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