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Review
. 2017 Nov;27(11):833-850.
doi: 10.1016/j.tcb.2017.07.006. Epub 2017 Aug 30.

Emerging Roles for the Lysosome in Lipid Metabolism

Ashley M Thelen  1 , Roberto Zoncu  2
Affiliations
Review

Emerging Roles for the Lysosome in Lipid Metabolism

Ashley M Thelen et al. Trends Cell Biol. 2017 Nov.

Abstract

Precise regulation of lipid biosynthesis, transport, and storage is key to the homeostasis of cells and organisms. Cells rely on a sophisticated but poorly understood network of vesicular and nonvesicular transport mechanisms to ensure efficient delivery of lipids to target organelles. The lysosome stands at the crossroads of this network due to its ability to process and sort exogenous and endogenous lipids. The lipid-sorting function of the lysosome is intimately connected to its recently discovered role as a metabolic command-and-control center, which relays multiple nutrient cues to the master growth regulator, mechanistic target of rapamycin complex (mTORC)1 kinase. In turn, mTORC1 potently drives anabolic processes, including de novo lipid synthesis, while inhibiting lipid catabolism. Here, we describe the dual role of the lysosome in lipid transport and biogenesis, and we discuss how integration of these two processes may play important roles both in normal physiology and in disease.

Keywords: cholesterol; lipid metabolism; lysosome; mTORC1; membrane contact sites.

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Figures

Fig. 1
Fig. 1. Cellular routes for cholesterol trafficking
Low-density lipoprotein receptors (LDLR) on the plasma membrane bind LDL particles and are delivered into early endosomes (EE) via clathrin-mediated endocytosis (1). As EE acidify and mature into late endosomes (LE), LDL dissociates from the LDLR and the LDLR is sorted into the endocytic recycling compartment (ERC) and returned to the plasma membrane. LDL continues along the endocytic pathway and ultimately reaches the lysosome (2), where the LDL is broken down (3). Lysosomal acid lipase (LipA) hydrolyzes cholesteryl esters to release free cholesterol. Cholesterol is shuttled through the lysosomal lumen by NPC2, and subsequently transferred to the luminal N-terminal domain of the polytopic transmembrane protein NPC1 (4). The mechanisms of cholesterol export from the lysosome are still unknown, although they are likely to occur through several parallel routes that may involve the formation of membrane contact sites (shown by bidirectional dashed lines) between the lysosome and acceptor membranes (5). Endogenous cholesterol synthesis at the endoplasmic reticulum (ER) requires multiple biosynthetic enzymes including the rate-limiting enzyme HMG-CoA reductase. Under conditions of cholesterol abundance, ER cholesterol can be esterified by Acetyl-CoA Acetyltransferase 1 (ACAT1) and stored in lipid droplets (6).
Fig. 2
Fig. 2. Lipid transfer proteins mediate lipid exchange between membranes
Sterols and phospholipids are transferred between two adjacent organelle membranes via lipid transfer proteins. ER anchored VAP serves as the interacting partner for various lipid transfer proteins including OSBP on the Golgi as well as ORP1L and STARD3 on the LE/LY. ORP1L and STARD3 are involved in cholesterol transfer from the LE/LY to the ER and from the ER to the LE/LY, respectively. ORP5 is a VAP-independent ER associated protein that interacts with NPC1 and is thought to act as a cholesterol acceptor, thus facilitating lysosomal cholesterol export. At the Golgi, OSBP transports PI4P down its concentration gradient to the ER, where the PI4P specific phosphatase Sac1 hydrolyzes it to PI to maintain low levels of PI4P at the ER membrane. After depositing the PI4P at the ER, OSBP binds cholesterol and transfers it to the Golgi, thus completing the cycle and establishing a net transfer of cholesterol in the ER-to-Golgi direction.
Fig. 3
Fig. 3. mTORC1 activation promotes lipid biogenesis and suppresses lipid catabolism
In the presence of nutrients, mTORC1 translocates from the cytoplasm to the surface of the lysosome where it becomes activated and phosphorylates downstream substrates thereby activating (green box) or inhibiting them (red box). S6-kinase 1 (S6K1) is an mTORC1 substrate that promotes proteolytic processing of the transcription factors SREBP1/2. Inactive, full-length SREBP is retained at the ER membrane by its association with SCAP and INSIG in the presence of cholesterol. Under low cholesterol conditions in the ER, SCAP undergoes a conformational change releasing SREBP and promoting its COPII vesicle mediated trafficking to the Golgi. At the Golgi, two proteases, S1P and S2P, cleave SREBP to release the soluble, N-terminal fragment, which translocates to the nucleus and binds to sterol response elements (SRE) upstream of promoters for genes involved in sterol uptake and de novo lipid biosynthesis. Furthermore, mTORC1 phosphorylation blocks the nuclear entry of lipin1, a phosphatidic acid phosphatase that acts as an inhibitor of nuclear SREBP activity. Similarly, phosphorylation of TFEB prevents its translocation to the nucleus, repressing transcriptional activation of CLEAR genes involved in β-oxidation of fatty acids, lipid catabolism, and lysosomal biogenesis. mTORC1 is thought to promote adipocyte differentiation by releasing a translational block mediated by 4E-BP1. Finally, mTORC1 inhibits autophagic degradation of lipid droplets through phosphorylation of ULK1 kinase.
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