A Mammalian Target of Rapamycin‐Perilipin 3 (mTORC1‐Plin3) Pathway is essential to Activate Lipophagy and Protects Against Hepatosteatosis

Abstract

Reporting of In Vivo Experiments AST Aspartate aminotransferase αSMA α-smooth muscle actin ATG16L Autophagy Related 16L ATG7 Autophagy Related 7 AAV Adeno-associated virus BODIPY 4,4-difluoro-4-bora-3a,4a-diaza-s-indacene BNIP BCL2 interacting protein 3 BNIP3L/NIX BCL2 interacting protein 3 like BBVA Banco Bilbao Vizcaya Argentaria°C Celsius Degrees CCPG1 Cell-Cycle Progression Gene 1 CMA Chaperon Mediated Autophagy Co-IP Co-Immuno Precipitation Col1a1 Type IA1 collagen CPT1 Carnitine PalmitoylTransferase I Ctrl Control Financial support: This work was supported by C0120R3166, C0245R4032 and BH182173 from Newcastle University. MG-M is a Sara Borrell Postdoctoral fellow (CD18/00203

Ethyl 2-[2,3,4-Trimethoxy-6-(1-Octanoyl)Phenyl] Acetate (TMPA) Ameliorates Lipid Accumulation by Disturbing the Combination of LKB1 with Nur77 and Activating the AMPK Pathway in HepG2 Cells and Mice Primary Hepatocytes

“…Therefore, liver fat metabolism is closely associated with lipophagy. 26,27 Lipophagy is a type of autophagy, and its activation can reduce lipid deposition by phagocytosis of lipid droplets in the cytoplasm and lysozyme formation.…”

“…28 Activation of AMPK inhibits m-TOR through the phosphorylation pathway. 27 Therefore, we consider that TMPA may have the function that inhibits m-TOR activity through phosphorylation by activating the LKB1-AMPK axis, and in turn activate lipophagy to increase fatty acid decomposition.…”

Touch and Go: Membrane Contact Sites Between Lipid Droplets and Other Organelles

“…PLIN2 functions in LD biogenesis, stability and trafficking and serves as a scaffold that regulates association of LDs with the macroautophagy machinery ( Tsai et al, 2017 ). PLIN3 also regulates macroautophagy in a TORC1 (target of rapamycin 1) -dependent manner ( Garcia-Macia et al, 2021 ). Starvation-induced CMA of PLIN2 and PLIN3 is mediated by the 70-kD heat shock protein, hsc70, which binds to the pentapeptide motifs LDRLQ on PLIN2 and SLKVQ on PLIN3, promotes phosphorylation of PLIN2 by 5′ AMP-activated protein kinase (AMPK), and delivers PLIN2 and PLIN3 to the lysosome-associated membrane protein 2A (LAMP2A) ( Kaushik and Cuervo, 2015 ; 2016 ; 2018 ), the vacuolar membrane protein that facilitates translocation of CMA substrates from the lysosomal surface to the lumen ( Chiang et al, 1989 ; Salvador et al, 2000 ; Bandyopadhyay and Cuervo, 2008 ).…”

The roles of autophagy and thyroid hormone in the pathogenesis and treatment of NAFLD

“…These modifications activate CHKα2 and phosphorylate LD membrane proteins, perilipin 2 (PLIN2) and 3 (PLIN3). The phosphorylation of PLIN2/3 dissociates PLIN2/3 from LD for CMA-mediated degradation [23] .…”

“…Lipophagy activation also requires recruitment of autophagy machinery to the LD, a process that is abolished in PLIN3 knockdown cells. PLIN3 indeed directly interacts with autophagy proteins Fip200 and Atg16L [ 24 ] . IFGGA2 is an immunity-related GTPase which co-localizes with ATGL and LC3B on LDs when animals are fed a high fat diet (HFD).…”