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

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.

Consumption of whole eggs promotes greater stimulation of postexercise muscle protein synthesis than consumption of isonitrogenous amounts of egg whites in young men

“…(1,5,11,12), may also have a role in modulating the postprandial muscle protein synthetic response in healthy adults. For example, as part of its whole-food matrix, the egg yolk contains various nonprotein food components that may have anabolic properties, such microRNAs (33), vitamins (34,35), minerals (36), and lipids [e.g., phosphatidic acid (37), palmitic acid (38), and DHA (39)] by modifying pathways related to transcriptional or protein translational control. However, more work is required to systematically assess the role of such food components on modulating postprandial muscle protein synthesis rates in vivo in humans.…”

Impaired Podocyte Autophagy Exacerbates Proteinuria in Diabetic Nephropathy

“…The mouse podocyte cell line was cultured as previously described (27,28). Differentiated cells were stimulated with high glucose (500 mg/dL), fatty acids (palmitate and oleate, 150 mmol/L each), tumor necrosis factor-a (TNFa, 10 ng/mL), or serum for 24 h. Sera were collected from the indicated rodent models and patients.…”

Endoplasmic reticulum stress in kidney function and disease

“…Uzu and colleagues found that saturated free fatty acids such as palmitate activated mTORC1, suppressed autophagy and induced ER stress-dependent apoptosis in podocytes. Interestingly, unsaturated free fatty acids including oleate showed the opposite effects and ameliorated palmitate-induced ER stress and apoptosis [24]. Dong et al [25] reported that mTORC1 was rapidly activated during ER stress and involved in ER stressinduced apoptosis of renal proximal tubular cells, possibly by suppressing autophagy.…”