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Review
. 2021 Aug:50:101146.
doi: 10.1016/j.molmet.2020.101146. Epub 2021 Jan 5.

Function of the endolysosomal network in cholesterol homeostasis and metabolic-associated fatty liver disease (MAFLD)

Dyonne Y Vos  1 , Bart van de Sluis  2
Affiliations
Review

Function of the endolysosomal network in cholesterol homeostasis and metabolic-associated fatty liver disease (MAFLD)

Dyonne Y Vos et al. Mol Metab. 2021 Aug.

Abstract

Background: Metabolic-associated fatty liver disease (MAFLD), also known as non-alcoholic fatty liver disease, has become the leading cause of chronic liver disease worldwide. In addition to hepatic accumulation of triglycerides, dysregulated cholesterol metabolism is an important contributor to the pathogenesis of MAFLD. Maintenance of cholesterol homeostasis is highly dependent on cellular cholesterol uptake and, subsequently, cholesterol transport to other membrane compartments, such as the endoplasmic reticulum (ER).

Scope of review: The endolysosomal network is key for regulating cellular homeostasis and adaptation, and emerging evidence has shown that the endolysosomal network is crucial to maintain metabolic homeostasis. In this review, we will summarize our current understanding of the role of the endolysosomal network in cholesterol homeostasis and its implications in MAFLD pathogenesis.

Major conclusions: Although multiple endolysosomal proteins have been identified in the regulation of cholesterol uptake, intracellular transport, and degradation, their physiological role is incompletely understood. Further research should elucidate their role in controlling metabolic homeostasis and development of fatty liver disease.

Keywords: Cholesterol transport; Endosomal sorting; Endosome and lysosome; LDLR; NAFLD; PCSK9.

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Figures

Figure 1
Figure 1
Cholesterol transport through the endolysosomal network. After binding to LDLR, LDL-cholesterol is internalized, and the LDL-LDLR complex is transported to endosomes, where LDL-cholesterol dissociates from LDLR. LDLR can be transported back to the plasma membrane via recycling endosomes (RE). LDL-cholesterol is transported to late endosome/lysosome (LE/LY), where lysosomal acid lipase (LAL) hydrolyzes cholesterol esters to release free cholesterol. TPC2 is important for LE-LY fusion and thus for further cholesterol transport. NPC2 can bind and deliver free cholesterol to NPC1. NPC1 regulates cholesterol transport to other cellular compartments, such as the endoplasmic reticulum (ER) by interacting with Rab7 and the plasma membrane via Rab8a. The ER-located RNF26 recruits and ubiquitinates p62, leading to the binding of specific endosomal-associated adaptor proteins to mediate the positioning of vesicles in the perinuclear area, but its function in cholesterol transport needs to be elucidated. Gramd1b, or Aster-B, is implicated in both LE/LY-to-PM and PM-to-ER cholesterol transport. When cholesterol levels in the ER are low, SREBP is translocated to the nucleus, where it induces transcription of genes involved in lipogenesis and cholesterol uptake and synthesis. Cholesterol levels in LE/LY affect lysosomal function and thereby also the autophagic pathway, in which p62 is an important player. Rab24 is thought to reduce autophagy and thereby contribute to MAFLD. The endosomal WASH complex and the retromer subunit VPS35 are also known to affect autophagy, but their physiological role in this context and in MAFLD remain unknown.
Figure 2
Figure 2
Working model of endosomal trafficking of LDLR. Following endocytosis, LDLR is transported to endosomes, where the receptor is directed to the late endosomes and lysosomes for PCSK9- or IDOL-mediated degradation or is retrieved from this pathway and recycled back to the plasma membrane. The CCC complex is known to facilitate recycling of LDLR by a direct interaction between CCC subunit COMMD1 with LDLR, whereas WASH drives formation of actin patches on endosomal sorting domains to regulate LDLR recycling. Although the function of retromer and retriever in LDLR recycling has not been fully elucidated, retromer might facilitate LDLR recycling by recruiting CCC and WASH complexes to the endosomal membrane, and retriever might regulate LDLR retrieval and recycling by coupling to SNX17, an adaptor protein binding to the NPxY-motif in the cytosolic tail of LDLR. ESCRT = endosomal sorting complex required for transport; Ub = ubiquitin.
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