Involvement of FATP2-mediated tubular lipid metabolic reprogramming in renal fibrogenesis

Abstract

Following a chronic insult, renal tubular epithelial cells (TECs) contribute to the development of kidney fibrosis through dysregulated lipid metabolism that lead to lipid accumulation and lipotoxicity. Intracellular lipid metabolism is tightly controlled by fatty acids (FAs) uptake, oxidation, lipogenesis, and lipolysis. Although it is widely accepted that impaired fatty acids oxidation (FAO) play a crucial role in renal fibrosis progression, other lipid metabolic pathways, especially FAs uptake, has not been investigated in fibrotic kidney. In this study, we aim to explore the potential mechanically role of FAs transporter in the pathogenesis of renal fibrosis. In the present study, the unbiased gene expression studies showed that fatty acid transporter 2 (FATP2) was one of the predominant expressed FAs transport in TECs and its expression was tightly associated with the decline of renal function. Treatment of unilateral ureteral obstruction (UUO) kidneys and TGF-β induced TECs with FATP2 inhibitor (FATP2i) lipofermata restored the FAO activities and alleviated fibrotic responses both in vivo and in vitro. Moreover, the expression of profibrotic cytokines including TGF-β, connective tissue growth factor (CTGF), fibroblast growth factor (FGF), and platelet-derived growth factor subunit B (PDGFB) were all decreased in FATP2i-treated UUO kidneys. Mechanically, FATP2i can effectively attenuate cell apoptosis and endoplasmic reticulum (ER) stress induced by TGF-β treatment in cultured TECs. Taking together, these findings reveal that FATP2 elicits a profibrotic response to renal interstitial fibrosis by inducing lipid metabolic reprogramming including abnormal FAs uptake and defective FAO in TECs.

Targeting Gremlin 1 Prevents Intestinal Fibrosis Progression by Inhibiting the Fatty Acid Oxidation of Fibroblast Cells

“…We consistently observed significant numbers of lipid droplets and enhanced FAO in intestinal fibroblast cells upon GREM1 treatment. On the other hand, Chung et al (Chen et al, 2020) reported that the expression of FAO-associated enzymes in renal tubule epithelium is reduced in aged rat kidneys. This facilitates the progression of renal fibrosis indicating that FAO alterations in fibroblast and epithelial cells affect the progression of fibrosis differently.…”

“…Rapid growth and ECM deposition require a huge amount of energy. Previous studies reported that fibroblasts could reprogram their metabolism by enhancing glycolysis and FAO to sustain cell proliferation and activation (Schreurs et al, 2010;Latella and Papi, 2012;Latella et al, 2014;Qu et al, 2016;Khomich et al, 2019;Chen et al, 2020). In kidney stromal cells, Interleukin-1β induced glycolysis enhancement is necessary for progressive tubulointerstitial fibrosis (Lemos et al, 2018).…”

Metabolic Reprogramming and Renal Fibrosis

“…Cells then transport acyl CoA into the mitochondria via carnitine acyltransferase I and II, and FAO produces acetyl CoA ( 51 ), a fuel for the tricarboxylic acid (TCA) cycle and OXPHOS ( 52 ). Lipid synthesis and catabolism are highly regulated in healthy renal tubular epithelial cells ( 53 ). However, an imbalance between FA intake and utilization can lead to lipid accumulation and kidney damage ( 54 ).…”

Lipid Disorders in NAFLD and Chronic Kidney Disease

“…Given the high volume of blood that passes through, the kidney is also easily affected by the amount of circulating FFA from lipolysis in adipocytes [27]. In vivo data suggest that FATP2 regulates proximal tubule apical non-esterified fatty acids (NEFA) uptake and could be the crucial inciting factor for kidney fibrosis development [28,29]. Besides, CD36 knockout mice fed an HFD displayed lower renal lipid accumulation and had less glomerular and tubulointerstitial macrophage accumulation, foam cell formation, oxidant stress and interstitial fibrosis [30].…”