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Carbohydrate response element‐binding protein regulates lipid metabolism via mTOR complex1 in diabetic nephropathy
Author(s) -
Chen Nan,
Mu Lin,
Yang Zhifen,
Du Chunyang,
Wu Ming,
Song Shan,
Yuan Chen,
Shi Yonghong
Publication year - 2021
Publication title -
journal of cellular physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.529
H-Index - 174
eISSN - 1097-4652
pISSN - 0021-9541
DOI - 10.1002/jcp.29890
Subject(s) - carbohydrate responsive element binding protein , fatty acid synthase , txnip , mtorc1 , lipid metabolism , medicine , endocrinology , lipogenesis , diabetic nephropathy , chemistry , carbohydrate metabolism , downregulation and upregulation , transcription factor , pi3k/akt/mtor pathway , biology , kidney , oxidative stress , biochemistry , signal transduction , thioredoxin , gene
Lipid deposition caused by the disorder of renal lipid metabolism is involved in diabetic nephropathy (DN). Carbohydrate response element‐binding protein (ChREBP) is a key transcription factor in high glucose‐induced cellular fat synthesis. At present, the regulation and mechanism of ChREBP on fat metabolism in diabetic kidneys are still unclear. In this study, we showed that lack of ChREBP significantly improved renal injury, inhibited oxidative stress, lipid deposition, fatty acid synthase (FASN), acetyl‐CoA carboxylase (ACC) and thioredoxin‐interacting protein (TXNIP) expression, as well as the activity of mammalian target of rapamycin complex 1 (mTORC1) in diabetic kidneys. Meanwhile, ChREBP deficiency upregulated the expression of peroxisome proliferator‐activated receptor‐α (PPARα), carnitine palmitoyltransferaser 1A (CPT1A) and acyl‐coenzyme A oxidase 1 (ACOX1) in diabetic kidneys. In vitro, knockdown of ChREBP attenuated lipid deposition, mTORC1 activation, and expression of FASN and ACC, increased PPARα, CPT1A, and ACOX1 expression in HK‐2 cells and podocytes under high glucose (HG) conditions. Moreover, HG‐induced lipid deposition, increased expression of FASN and ACC and decreased expression of PPARα, CPT1A, and ACOX1 were reversed by rapamycin, a specific inhibitor of mTORC1, in HK‐2 cells. These results indicate that ChREBP deficiency alleviates diabetes‐associated renal lipid accumulation by inhibiting mTORC1 activity and suggest that reduction of ChREBP is a potential therapeutic strategy to treat DN.