Cholesterol Transport through Lysosome-Peroxisome Membrane Contacts

Acetyl-CoA Derived from Hepatic Peroxisomal β-Oxidation Inhibits Autophagy and Promotes Steatosis via mTORC1 Activation

“…Western blot analysis indicated that Raptor acetylation was significantly decreased, while acetylation of histone H3 was unaffected by Acox1 knockout (Figures 4F and 4G), suggesting that peroxisome-derived acetyl CoA might have a selective role in acetylation. In this regard, previous studies suggest that lysosomes form membrane contacts with peroxisomes (Chu et al, 2015). Notably, immunofluorescence analysis using antibodies against peroxisomal and lysosomal markers indicated that fasting promotes colocalization of peroxisomes with lysosomes in the liver (Figures 4H and 4I), raising the possibility that lysosome-associated Raptor might undergo acetylation mediated by locally generated peroxisomal acetyl-CoA.…”

Organelle interplay—peroxisome interactions in health and disease

“…47 Plasma membranes are also highly enriched in cholesterol comprising up to 65% to 80% of the total cellular content, while minute amounts of 0.5% to 1% are found in the ER membrane 48 and an intermediate proportion of 5% has been estimated for peroxisomes. 49 PIs represent a heterogeneous group of important cellular signaling molecules which are distinguished by the phosphorylation state of their inositol head group and show a compartmentspecific distribution. The phosphorylation state determines their function, modulates their interaction partners and thus the signaling pathways they participate in.…”

“…Indeed, peroxisomal membrane contacts with lysosomes (LPMC) appear to be less frequent than those with the ER or mitochondria, but still comprise around 15% to 20% of the total peroxisome number in mammalian cells. 4,49 However, as LPMC formation is of transient nature, contact frequencies can change in response to different stimuli. Incubation of Hela cells with LDL (low-density lipoprotein), delivering lipids to the cell, increased LPMC in a timedependent manner implying that LPMC form in a tightly controlled process in order to transfer specific metabolites.…”

“…Incubation of Hela cells with LDL (low-density lipoprotein), delivering lipids to the cell, increased LPMC in a timedependent manner implying that LPMC form in a tightly controlled process in order to transfer specific metabolites. 49 The metabolic significance of LPMCs was detected in an RNAi screen for genes associated with lysosomal cholesterol transport deficiencies. 49 Cholesterol is synthesized de novo by a pathway shared by the ER, mitochondria and the cytosol, or taken up by food consumption where it is delivered to the target cells via LDL, which under normal conditions is the dominant route of cellular cholesterol supply.…”

CRISPR screens for lipid regulators reveal a role for ER-bound SNX13 in lysosomal cholesterol export

“…Gruenberg and colleagues presented an siRNA screen that detected a connection with Wnt signaling (Scott et al, 2016). Trinh et al (2020) measured surface LDLR levels; van den Boomen et al (2020) employed a synthetic reporter to monitor SREBP transcriptional activation; and Chu et al (2015) used amphotericin to kill cells that succeeded in plasma membrane cholesterol delivery. Use of different approaches will surely yield different overall hit profiles.…”