Objective: Ectopic lipid accumulation in the liver and kidneys is a hallmark of metabolic diseases leading to non-alcoholic fatty liver disease (NAFLD) and chronic kidney disease (CKD). Moreover, recent data have highlighted a strong correlation between NAFLD and CKD incidences. In this study, we use two mouse models of hepatic steatosis or CKD, each initiated independently of the other upon the suppression of glucose production specifically in the liver or kidneys, to elucidate the mechanisms underlying the development of CKD in the context of NAFLD-like pathology. Methods: Mice with a deletion of G6pc, encoding glucose-6 phosphatase catalytic subunit, specifically in the liver (L.G6pc−/− mice) or the kidneys (K.G6pc−/− mice), were fed with either a standard diet or a high fat/high sucrose (HF/HS) diet during 9 months. These mice represent two original models of a rare metabolic disease named Glycogen Storage Disease Type Ia (GSDIa) that is characterized by both NAFLD-like pathology and CKD. Two other groups of L.G6pc−/− and K.G6pc−/− mice were fed a standard diet for 6 months and then treated with fenofibrate for 3 months. Lipid and glucose metabolisms were characterized, and NAFLD-like and CKD damages were evaluated. Results: Lipid depot exacerbation upon high-calorie diet strongly accelerated hepatic and renal pathologies induced by the G6pc-deficiency. In L.G6pc−/− mice, HF/HS diet increased liver injuries, characterized by higher levels of plasmatic transaminases and increased hepatic tumor incidence. In K.G6pc−/− mice, HF/HS diet increased urinary albumin and lipocalin 2 excretion and aggravated renal fibrosis. In both cases, the worsening of NAFLD-like injuries and CKD was independent of glycogen content. Furthermore, fenofibrate, via the activation of lipid oxidation significantly decreased the hepatic or renal lipid accumulations and prevented liver or kidney damages in L.G6pc−/− and K.G6pc−/− mice, respectively. Finally, we show that L.G6pc−/− mice and K.G6pc−/− mice developed NAFLD-like pathology and CKD independently. Conclusions: This study highlights the crucial role that lipids play in the independent development of both NAFLD and CKD and demonstrates the importance of lipid-lowering treatments in various metabolic diseases featured by lipid load, from the “rare” GSDIa to the “epidemic” morbid obesity or type 2 diabetes.
Monteillet, L., Gjorgjieva, M., Silva, M., Verzieux, V., Imikirene, L., Duchampt, A., … Rajas, F. (2018). Intracellular lipids are an independent cause of liver injury and chronic kidney disease in non alcoholic fatty liver disease-like context. Molecular Metabolism, 16, 100–115. https://doi.org/10.1016/j.molmet.2018.07.006