2020
DOI: 10.1038/s41598-020-78376-1
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Saturated fatty acids induce insulin resistance in podocytes through inhibition of IRS1 via activation of both IKKβ and mTORC1

Abstract: Diabetic nephropathy (DN), a microvascular complication of diabetes, is the leading cause of end-stage renal disease worldwide. Multiple studies have shown that podocyte dysfunction is a central event in the progression of the disease. Beside chronic hyperglycemia, dyslipidemia can induce insulin resistance and dysfunction in podocytes. However, the exact mechanisms of free fatty acid (FFA)-induced podocyte insulin unresponsiveness are poorly understood. We used a type 2 diabetic mouse model (db/db) and mouse … Show more

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Cited by 17 publications
(9 citation statements)
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“…Sequestration of fatty acids in liver, kidney, pancreas, skeletal muscle, and gastrointestinal systems leads to lipotoxicity, impairment of energy metabolism, and further progression of kidney disease (26). Recent reports show that saturated fatty acids can also directly cause insulin resistance in podocytes (27) and in tubular epithelial cells (28) and directly contribute to their impaired energy metabolism and hence CKD progression. The clinical implication is that lipid alteration is dependent on the CKD stage, and its values should be interpreted in the context of the corresponding stage.…”
Section: Discussionmentioning
confidence: 99%
“…Sequestration of fatty acids in liver, kidney, pancreas, skeletal muscle, and gastrointestinal systems leads to lipotoxicity, impairment of energy metabolism, and further progression of kidney disease (26). Recent reports show that saturated fatty acids can also directly cause insulin resistance in podocytes (27) and in tubular epithelial cells (28) and directly contribute to their impaired energy metabolism and hence CKD progression. The clinical implication is that lipid alteration is dependent on the CKD stage, and its values should be interpreted in the context of the corresponding stage.…”
Section: Discussionmentioning
confidence: 99%
“…showed that palmitic acid‐induced inhibition of insulin signaling in podocytes is associated with Ser307 phosphorylation of IRS‐1. Thus, inhibitors of IKK, mTOR, and ceramide can blunt IRS‐1 Ser307 phosphorylation and restore insulin stimulation of Akt 41 (Figure 2). Moreover, targeting mTOR in PI3K/Akt pathway has also been indicated beneficial in MS.…”
Section: Proteins That Physically Interact With Akt As Its Downstream...mentioning
confidence: 99%
“…However, the degree of phosphorylation of the mTORC1 inhibitor, PRAS40 (Thr246), and its substrate, p70S6K (Thr389) was higher in the blood cells of diabetic patients 40 . Saturated free fatty acids activate mTORC1/S6K1 and serine/threonine kinase IκB kinase (IKK)β/IκBα, but not c‐JNK and PKC in podocyte and glomeruli of db/db mice 41 . showed that palmitic acid‐induced inhibition of insulin signaling in podocytes is associated with Ser307 phosphorylation of IRS‐1.…”
Section: Proteins That Physically Interact With Akt As Its Downstream...mentioning
confidence: 99%
See 1 more Smart Citation
“…The phosphorylation of insulin receptor substrate-1 (IRS1), a mediator protein that links the binding of insulin and insulin growth factor 1 to related intracellular receptors of the insulin pathways, can activate ceramides to lead to impaired islet signaling ( 145 ). The increased IRS1 level induces serine 307 phosphorylation to inhibit insulin signaling ( 146 ). Ceramides can also suppress IRS1 expression by triggering the PKR/JNK/Prep1/p160 axis and/or the c-Jun amino-terminal kinase/PBX regulatory protein 1 axis ( 89 ).…”
Section: Mechanism Of Ceramides In Diabetesmentioning
confidence: 99%