Autophagy and Lipid Droplets in the Liver

Abstract

Autophagy is a conserved quality-control pathway that degrades cytoplasmic contents in lysosomes. Autophagy degrades lipid droplets through a process termed lipophagy. Starvation and an acute lipid stimulus increase autophagic sequestration of lipid droplets and their degradation in lysosomes. Accordingly, liver-specific deletion of the autophagy gene Atg7 increases hepatic fat content, mimicking the human condition termed nonalcoholic fatty liver disease. In this review, we provide insights into the molecular regulation of lipophagy, discuss fundamental questions related to the mechanisms by which autophagosomes recognize lipid droplets and how ATG proteins regulate membrane curvature for lipid droplet sequestration, and comment on the possibility of cross talk between lipophagy and cytosolic lipases in lipid mobilization. Finally, we discuss the contribution of lipophagy to the pathophysiology of human fatty liver disease. Understanding how lipophagy clears hepatocellular lipid droplets could provide new ways to prevent fatty liver disease, a major epidemic in developed nations.

Keywords: lipases; lipophagy; lysosome; metabolism; steatosis.

Figure 1

The autophagy pathway. Stress or starvation activates the class III phosphatidylinositol 3-kinases (PI3K) complex that generates phosphatidylinositol 3-phosphates (PI3Ps). PI3Ps recruit autophagy genes (ATGs) to the nucleation complex including UNC51-like kinase 1 (ULK1), an upstream regulator of autophagy. Two conjugation cascades, i.e., the ATG12-ATG5 and light chain 3 (LC3) conjugation cascades, are activated, which results in lipidation of cytosolic LC3-I into membrane-bound LC3-II. LC3-II-positive autophagosomes sequester cytoplasmic cargo that is delivered to the lysosomes, wherein a battery of acid hydrolases degrade engulfed cargo. Products of degradation—amino acids, fatty acids, and nucleic acids—are utilized by the starved cell. Abbreviations: AMBRA1, activating molecule in Beclin1-regulated autophagy; Beclin1, coiled-coil, myosin-like BCL2-interacting protein; Dynein HC, dynein heavy chain; P-mTOR, phospho-mammalian target of rapamycin; P-ULK1, phospho-UNC51-like kinase 1.

Figure 2

The regulation of lipophagy. The availability of nutrients phosphorylates and activates the mechanistic target of rapamycin (mTOR). It is likely that lysosomal efflux of amino acids also activates mTOR. Active mTOR phosphorylates transcription factor EB (TFEB) and retains it in the cytoplasm, and it decreases autophagy and lysosomal gene expression. Active mTOR also suppresses UNC51-like kinase 1 (ULK1) activity by phosphorylating ULK1 at SER 757. During nutrient depletion, mTOR is inactivated while adenosine monophosphate-activated protein kinase (AMPK) is activated. These events allow ULK1 phosphorylation at SER 555, which results in ULK1 activation. Suppression of mTOR activity also allows TFEB to localize to the nucleus to drive autophagy and lysosomal gene expression. Activation of autophagy begins to sequester and degrade lipid droplets (LDs) in lysosomes. Lysosome-derived free fatty acids are oxidized in the mitochondria for production of adenosine triphosphate (ATP).