Fatty acids are novel nutrient factors to regulate mTORC1 lysosomal localization and apoptosis in podocytes

Biochim Biophys Acta. 2014 Jul;1842(7):1097-108. doi: 10.1016/j.bbadis.2014.04.001. Epub 2014 Apr 13.

Abstract

Podocyte apoptosis is a potent mechanism of proteinuria in diabetic nephropathy. More detailed mechanistic insight into podocyte apoptosis is needed to better understand the pathogenesis of diabetic nephropathy. An elevated level of serum free fatty acid (FFA), as well as hyperglycemia, is a clinical characteristic in diabetes, although its causal role in podocyte apoptosis remains unclear. This study examined the effect of three types of FFAs, saturated, monounsaturated and polyunsaturated FFAs, on podocyte apoptosis. Palmitate, a saturated FFA, induced endoplasmic reticulum (ER) stress-dependent apoptosis in podocytes. Oleate, a monounsaturated FFA, and eicosapentaenoic acid (EPA), an ω-3 polyunsaturated FFA did not induce apoptosis; rather, they antagonized palmitate-induced apoptosis. Palmitate activated mammalian target of rapamycin (mTOR) complex 1 (mTORC1), a nutrient-sensing kinase regulating a wide range of cell biology. Furthermore, inhibition of mTORC1 activity by rapamycin or siRNA for Raptor, a component of mTORC1, ameliorated palmitate-induced ER stress and apoptosis in podocytes. Activity of mTORC1 is regulated by upstream kinases and Rag/Ragulator-dependent recruitment of mTOR onto lysosomal membranes. Palmitate activated mTORC1 by enhancing recruitment of mTOR onto lysosomal membranes, which was inhibited by co-incubation with oleate or EPA. Inhibition of mTOR translocation onto lysosomes by transfection with dominant-negative forms of Rag ameliorated palmitate-induced apoptosis. This study suggests that saturated and unsaturated FFAs have opposite effects on podocyte apoptosis by regulating mTORC1 activity via its translocation onto lysosomal membranes, and the results provide a better understanding of the pathogenesis in diabetic nephropathy and a novel role of mTORC1 in cell apoptosis.

Keywords: Diabetic nephropathy; Free fatty acid; Lysosome; Podocyte apoptosis; mTORC1.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / physiology*
  • Cell Line
  • Diabetic Nephropathies / metabolism
  • Eicosapentaenoic Acid / metabolism
  • Endoplasmic Reticulum Stress / physiology
  • Fatty Acids / metabolism*
  • Food
  • HEK293 Cells
  • Humans
  • Lysosomes / metabolism*
  • Mechanistic Target of Rapamycin Complex 1
  • Mice
  • Multiprotein Complexes / metabolism*
  • Oleic Acid / metabolism
  • Palmitates / metabolism
  • Podocytes / metabolism*
  • TOR Serine-Threonine Kinases / metabolism*

Substances

  • Fatty Acids
  • Multiprotein Complexes
  • Palmitates
  • Oleic Acid
  • Eicosapentaenoic Acid
  • TOR Serine-Threonine Kinases
  • Mechanistic Target of Rapamycin Complex 1