br Autophagy and lipid metabolism LD formation is an
Autophagy and lipid metabolism LD formation is an indispensable step in lipid metabolism. The Atg8/LC3 conjugation system is essential for autophagosome membrane formation. However, some evidence suggests that Atg8/LC3 conjugation is also involved in LD formation. Indeed, LD formation is suppressed in autophagy-deficient hepatocytes. As discussed above, the ubiquitin-like protein Atg8 also mediates the tethering and hemifusion of liposomes. However, it is not clear whether Atg8/LC3 is required for LD-LD fusion. Notably, TGs and cholesterol in LDs could also be taken up by autophagosomes and delivered to lysosomes for degradation by acidic hydrolases through selective autophagy. This alternative lipid metabolism pathway has been described and termed lipophagy, in Metabolism Compound Library to the typical pathway via cytoplasmic neutral hydrolases. Autophagic removal of excess hepatic LDs has been demonstrated in mice that were fed a high fat diet or challenged with alcohol, two common causes that induce non-alcoholic fatty liver disease and alcoholic fatty liver disease, respectively. Impaired lipophagy in liver exacerbates fatty liver disease. In contrast, autophagy activation attenuates fatty liver in both non-alcoholic fatty liver disease and alcoholic fatty liver disease. How autophagy selectively removes excess LDs is still largely unknown. A recent study demonstrated that the small GTPase Rab7 is indispensable for LD breakdown in hepatocytes subjected to nutrient deprivation. Starvation activates Rab7, which promotes trafficking of both multivesicular bodies and lysosomes to the LD surface during lipophagy, resulting in formation of a lipophagic synapse. Genetic knockdown of Rab7 leads to gross morphological changes in the multivesicular bodies, lysosomes, and autophagosomes, resulting in the attenuation of hepatocellular lipophagy. Future studies are needed to determine whether other autophagy receptor proteins, such as p62/SQSTM1, are involved in selective lipophagy. In addition to autophagy (macroautophagy), chaperone-mediated autophagy (CMA), a type of autophagy that selectively degrades a subset of cytosolic proteins in lysosomes, has also been shown to regulate LD biology and lipid homeostasis maintenance. CMA specifically degrades the LD-associated proteins perilipin (PLIN) 2 and PLIN3 prior to lipolysis. AMP-activated protein kinase phosphorylates PLIN2, priming the protein for its degradation by CMA. Inhibition of CMA leads to decreased association of adipose triglyceride lipase and lipophagy-related proteins with LDs, resulting in decreased lipid oxidation and LD accumulation. In addition to macroautophagy and CMA, the lysosome itself can also directly envelop cargo for degradation via microautophagy. However, the significance of microautophagy for LDs and lipid homeostasis remains largely elusive.
Autophagy and adipogenesis Adipocytes are derived from multipotent mesenchymal stem cells and require massive cytoplasmic remodeling. During adipogenesis of primary mouse embryonic fibroblasts, there is increased LC3-II and decreased p62/SQSTM1 protein expression and increased autophagic structures enclosing mitochondria and other organelles, indicating enhanced autophagy. Emerging evidence in cells and transgenic mice suggests that some genes that are critical in the autophagy process affect adipose tissue mass, differentiation, and physiological functions. The notion is supported by the following evidence: 1) Atg5 or Atg7 deficiency impairs adipogenesis in vitro and in vivo; 2) treatment with chloroquine, an autophagy inhibitor that increases lysosomal pH, inhibits adipogenesis in vitro; 3) mice with deletion of p62/SQSTM1, an autophagy substrate, develop mature-onset obesity and insulin resistance. Interestingly, upregulated autophagy genes and proteins have also been observed in human adipose tissue samples in obesity, although no autophagic flux data are available in obese human adipose tissue. Thus, the role of autophagy in adipose tissue, especially in a disease context, still requires further investigation.