TABLE 2.
Changes in lysosomal function associated with lipid overload
| Study Model | Effect on Lysosomes | Effect on Autophagy | Observation (Reference) |
| Mouse models of LSD (e.g., NPC1, MSD, and MPSIIIA) | Defective endocytic transport | Suppressed turnover due to defective autophagosome- lysosome fusion | Accumulation of unesterified cholesterol, phospholipids, glycolipids, sphingomyelin (115–117), dysfunctional mitochondria and polyubiquitinated proteins (123) |
| Reduced expression or activity of lysosomal hydrolases | |||
| Abnormal lysosomal pH | Aberrant sequestration of SNARE complex and accumulation of autophagic cargo (121, 125) | ||
| Enlarged lysosomal vesicles | |||
| Mouse models of diet-induced obesity and metabolic syndrome | Deficiency in Rab7 protein level | Suppressed autophagic flux linked to Rab7- or ER stress-dependent defects in autolysosome formation | Reduced Rab7 expression in the heart (85) |
| Enlarged lysosomal vesicles | Induced ER stress in liver (85, 156) | ||
| Accumulation of phospholipids, ubiquitinin, and p62-positive protein aggregates in lysosomes in kidney and liver (128, 156) | |||
| Mouse models of diet-induced LMP | Bax-induced permeabilization of lysosomal membrane | Suppressed autophagy due to lack of intact, functional lysosomes | Cytosolic cathepsin-induced apoptotic cell death (130, 136) |
| Release of cathepsin B, D and K into cytosol | Cathepsin-induced mitochondrial membrane permeabilization and apoptotic cell death (136) | ||
| Lipotoxic liver injury in nonalcoholic steatohepatitis (136) | |||
| Cardiac hypertrophy and contractile dysfunction (85, 86) | |||
| Impaired cholesterol efflux in macrophages (137) | |||
| Cell culture model of lipid-induced oxidative stress and lipotoxicity | Increased lysosomal pH | Suppressed due to inhibition of autophagosome turnover | Increased Nox2-derived superoxide production, s-nitrosylation of lysosomal v-ATPase, accumulation of defective autolysosomes (89) |
| Reduced lysosomal cathepsin activity | |||
| Oxidative posttranslational modification of lysosomal v-ATPase | |||
| Decreased lysosomal acidification | Suppressed due to reduced lysosomal acidification and hydrolase activity caused by low cellular ATP levels | Accumulation of autophagosomes and autophagic cargo, reduced mitochondrial oxidative phosphorylation and ATP production, and β-cell dysfunction marked by defective insulin secretion and increase cell death (64) | |
| Reduced cathepsin L activity | |||
| Bax-induced LMP | Unknown | Upregulation of ceramide and caspase dependent LMP and apoptotic cell death (130) |