The ménage à trois of autophagy, lipid droplets and liver disease.

ABSTRACT

Autophagic pathways cross with lipid homeostasis and thus provide energy and essential building blocks that are indispensable for liver functions. Energy deficiencies are compensated by breaking down lipid droplets (LDs), intracellular organelles that store neutral lipids, in part by a selective type of autophagy, referred to as lipophagy. The process of lipophagy does not appear to be properly regulated in fatty liver diseases (FLDs), an important risk factor for the development of hepatocellular carcinomas (HCC). Here we provide an overview on our current knowledge of the biogenesis and functions of LDs, and the mechanisms underlying their lysosomal turnover by autophagic processes. This review also focuses on nonalcoholic steatohepatitis (NASH), a specific type of FLD characterized by steatosis, chronic inflammation and cell death. Particular attention is paid to the role of macroautophagy and macrolipophagy in relation to the parenchymal and non-parenchymal cells of the liver in NASH, as this disease has been associated with inappropriate lipophagy in various cell types of the liver.Abbreviations ACAT acetyl-CoA acetyltransferase; ACAC/ACC acetyl-CoA carboxylase; AKT AKT serine/threonine kinase; ATG autophagy related; AUP1 AUP1 lipid droplet regulating VLDL assembly factor; BECN1/Vps30/Atg6 beclin 1; BSCL2/seipin BSCL2 lipid droplet biogenesis associated, seipin; CMA chaperone-mediated autophagy; CREB1/CREB cAMP responsive element binding protein 1; CXCR3 C-X-C motif chemokine receptor 3; DAGs diacylglycerols; DAMPs danger/damage-associated molecular patterns; DEN diethylnitrosamine; DGAT diacylglycerol O-acyltransferase; DNL de novo lipogenesis; EHBP1/NACSIN (EH domain binding protein 1); EHD2/PAST2 EH domain containing 2; CoA coenzyme A; CCL/chemokines chemokine ligands; CCl4 carbon tetrachloride; ER endoplasmic reticulum; ESCRT endosomal sorting complexes required for transport; FA fatty acid; FFAs free fatty acids; FFC high saturated fats, fructose and cholesterol; FGF21 fibroblast growth factor 21; FITM/FIT fat storage inducing transmembrane protein; FLD fatty liver diseases; FOXO forkhead box O; GABARAP GABA type A receptor-associated protein; GPAT glycerol-3-phosphate acyltransferase; HCC hepatocellular carcinoma; HDAC6 histone deacetylase 6; HECT homologous to E6-AP C-terminus; HFCD high fat, choline deficient; HFD high-fat diet; HSCs hepatic stellate cells; HSPA8/HSC70 heat shock protein family A (Hsp70) member 8; ITCH/AIP4 itchy E3 ubiquitin protein ligase; KCs Kupffer cells; LAMP2A lysosomal associated membrane protein 2A; LDs lipid droplets; LDL low density lipoprotein; LEP/OB leptin; LEPR/OBR leptin receptor; LIPA/LAL lipase A, lysosomal acid type; LIPE/HSL lipase E, hormone sensitive type; LIR LC3-interacting region; LPS lipopolysaccharide; LSECs liver sinusoidal endothelial cells; MAGs monoacylglycerols; MAPK mitogen-activated protein kinase; MAP3K5/ASK1 mitogen-activated protein kinase kinase kinase 5; MAP1LC3/LC3 microtubule associated protein 1 light chain 3; MCD methionine-choline deficient; MGLL/MGL monoglyceride lipase; MLXIPL/ChREBP MLX interacting protein like; MTORC1 mechanistic target of rapamycin kinase complex 1; NAFLD nonalcoholic fatty liver disease; NAS NAFLD activity score; NASH nonalcoholic steatohepatitis; NPC NPC intracellular cholesterol transporter; NR1H3/LXRα nuclear receptor subfamily 1 group H member 3; NR1H4/FXR nuclear receptor subfamily 1 group H member 4; PDGF platelet derived growth factor; PIK3C3/VPS34 phosphatidylinositol 3-kinase catalytic subunit type 3; PLIN perilipin; PNPLA patatin like phospholipase domain containing; PNPLA2/ATGL patatin like phospholipase domain containing 2; PNPLA3/adiponutrin patatin like phospholipase domain containing 3; PPAR peroxisome proliferator activated receptor; PPARA/PPARα peroxisome proliferator activated receptor alpha; PPARD/PPARδ peroxisome proliferator activated receptor delta; PPARG/PPARγ peroxisome proliferator activated receptor gamma; PPARGC1A/PGC1α PPARG coactivator 1 alpha; PRKAA/AMPK protein kinase AMP-activated catalytic subunit; PtdIns3K class III phosphatidylinositol 3-kinase; PtdIns3P phosphatidylinositol-3-phosphate; PTEN phosphatase and tensin homolog; ROS reactive oxygen species; SE sterol esters; SIRT1 sirtuin 1; SPART/SPG20 spartin; SQSTM1/p62 sequestosome 1; SREBF1/SREBP1c sterol regulatory element binding transcription factor 1; TAGs triacylglycerols; TFE3 transcription factor binding to IGHM enhancer 3; TFEB transcription factor EB; TGFB1/TGFß transforming growth factor beta 1; Ub ubiquitin; UBE2G2/UBC7 ubiquitin conjugating enzyme E2 G2; ULK1/Atg1 unc-51 like autophagy activating kinase 1; USF1 upstream transcription factor 1; VLDL very-low density lipoprotein; VPS vacuolar protein sorting; WIPI WD-repeat domain, phosphoinositide interacting; WDR WD repeat domain.