Metabolic Disorders

Autophagy and Metabolic Disorders

We have found that although CMA can only degrade intracellular proteins, it can contribute to the modulation of glucose and lipid metabolism through the selective degradation of key enzymes that regulate intracellular metabolic pathways. In support of this important role in metabolism regulation, we have found that mice with defective CMA develop a full blown metabolic syndrome when exposed to dietary challenges and that enhancement of CMA becomes protective against pro-atherogenic insults. The relationship between CMA and metabolism starts early in organ development as, for example, development of a fully mature adipose tissue requires functional CMA. Conversely, we have also found a profound impact of nutritional challenges on CMA activity and are currently exploring the possible use of chemical compounds that mimic dietary changes on the regulation of CMA.

Image by Dr Susmita Kaushik

  • Degradation of lipid droplet-associated proteins by chaperone-mediated autophagy facilitates lipolysis. Kaushik, S. Cuervo AM. Nat Cell Biol, 2015. doi: 10.1038/ncb3166

  • Loss of hepatic chaperone-mediated autophagy accelerates proteostasis failure in aging. Schneider S, Villarroya J, Diaz A, Patel B, Urbanska AM, Thi MM, Villarroya F, Santambrogio L, Cuervo AM. Aging Cell, 2015. doi: 10.1111/acel.12310

  • Deficient chaperone-mediated autophagy in liver leads to metabolic dysregulation. Schneider JL, Suh Y, Cuervo AM. Cell Metab, 2014. doi: 10.1016/j.cmet.2014.06.009

  • Rodriguez-Navarro JA, Kaushik S, Koga H, Dall’Armi, Shui G, Wenk MR, Di Paolo G, Cuervo AM*, Inhibitory effect of dietary lipids on chaperone-mediated autophagy. Proc. Natl. Acad. Sci. 109: E705-14, 2012.

  • Koga H, Kaushik S, Cuervo AM*, Altered lipid content inhibits autophagic vesicular fusion. FASEB J 24: 3052-65, 2010 1.

  • Singh, R.; Kaushik, S.; Wang, Y.; Xiang, Y.; Novak, I; Komatsu, M.; Tanaka, K.; Cuervo, A.M*.; Czaja, M.J*. Autophagy regulates lipid metabolism. Nature 458:1131-5, 2009

  • Kaushik, S.; Massey, A.C.; Kiffin, R., Cuervo, A.M*. Role of lysosomal lipid microdomains in the regulation of chaperone-mediated autophagy. EMBO J. 25, 3921-33, 2006