Abstract:Fatty acids (FAs) are critical nutrients that regulate an organism's health and development in mammal. Long-chain fatty acids (LCFAs) can be divided into saturated and unsaturated fatty acids, depending on whether the carbon chain contains at least 1 double bond. The fatty acids that are required for humans and animals are obtained primarily from dietary sources, and LCFAs are absorbed from outside of cells in mammals. LCFAs enter cells through several mechanisms, including passive diffusion and protein-mediat… Show more
“…Our study provides new insights into the beneficial effects of SGLT2 inhibition in diabetic kidney disease. (32,33) and fatty acid oxidation (34,35). Created with BioRender.com.…”
Approximately 40% of individuals with chronic kidney disease have type 2 diabetes mellitus, and diabetic kidney disease is the leading cause of end-stage kidney disease worldwide. Inhibitors of sodium-glucose cotransporter 2 (SGLT2) have been demonstrated to be effective in glucose control, improving cardiovascular outcomes and the progression of kidney disease. However, the protective role of SGLT2 inhibition on kidney metabolism is not fully understood. To explore these mechanisms further, we conducted analysis of publicly available single-cell RNA sequencing data of db/db mice treated with an SGLT2 inhibitor(dapagliflozin) and accompanying controls. We found that proximal tubule cells exhibited impaired glycolysis and high fatty acid oxidation in diabetes compared with control mice. SGLT2 inhibition reversed this metabolic dysfunction by reducing glycolysis and its substrate accumulation. SGLT2 inhibition also upregulates high fatty oxidation without increasing the uptake of fatty acids and elongation, along with low lipotoxicity. Surprisingly, both SGLT2(+) and SGLT2(-) cells show gene consistent changes in expression of metabolic genes, consistent with a non-cell autonomous effect of dapagliflozin treatment. This study demonstrates the protective role of SGLT2 inhibition via restoring metabolic dysfunction.
“…Our study provides new insights into the beneficial effects of SGLT2 inhibition in diabetic kidney disease. (32,33) and fatty acid oxidation (34,35). Created with BioRender.com.…”
Approximately 40% of individuals with chronic kidney disease have type 2 diabetes mellitus, and diabetic kidney disease is the leading cause of end-stage kidney disease worldwide. Inhibitors of sodium-glucose cotransporter 2 (SGLT2) have been demonstrated to be effective in glucose control, improving cardiovascular outcomes and the progression of kidney disease. However, the protective role of SGLT2 inhibition on kidney metabolism is not fully understood. To explore these mechanisms further, we conducted analysis of publicly available single-cell RNA sequencing data of db/db mice treated with an SGLT2 inhibitor(dapagliflozin) and accompanying controls. We found that proximal tubule cells exhibited impaired glycolysis and high fatty acid oxidation in diabetes compared with control mice. SGLT2 inhibition reversed this metabolic dysfunction by reducing glycolysis and its substrate accumulation. SGLT2 inhibition also upregulates high fatty oxidation without increasing the uptake of fatty acids and elongation, along with low lipotoxicity. Surprisingly, both SGLT2(+) and SGLT2(-) cells show gene consistent changes in expression of metabolic genes, consistent with a non-cell autonomous effect of dapagliflozin treatment. This study demonstrates the protective role of SGLT2 inhibition via restoring metabolic dysfunction.
“…Transporters involved in cardiomyocyte FA uptake include FA translocase (FAT/CD36), FA binding protein (FABPpm), and FA transport protein (FATP) ( 42 ). FABPpm works with CD36 to facilitate FA transmembrane transport of FAs ( 34 ).…”
Diabetic cardiomyopathy (DCM), one of the most serious complications of diabetes mellitus, has become recognized as a cardiometabolic disease. In normoxic conditions, the majority of the ATP production (>95%) required for heart beating comes from mitochondrial oxidative phosphorylation of fatty acids (FAs) and glucose, with the remaining portion coming from a variety of sources, including fructose, lactate, ketone bodies (KB) and branched chain amino acids (BCAA). Increased FA intake and decreased utilization of glucose and lactic acid were observed in the diabetic hearts of animal models and diabetic patients. Moreover, the polyol pathway is activated, and fructose metabolism is enhanced. The use of ketones as energy sources in human diabetic hearts also increases significantly. Furthermore, elevated BCAA levels and impaired BCAA metabolism were observed in the hearts of diabetic mice and patients. The shift in energy substrate preference in diabetic hearts results in increased oxygen consumption and impaired oxidative phosphorylation, leading to diabetic cardiomyopathy. However, the precise mechanisms by which impaired myocardial metabolic alterations result in diabetes mellitus cardiac disease are not fully understood. Therefore, this review focuses on the molecular mechanisms involved in alterations of myocardial energy metabolism. It not only adds more molecular targets for the diagnosis and treatment, but also provides an experimental foundation for screening novel therapeutic agents for diabetic cardiomyopathy.
“…Numerous studies have shown that the upregulation of FAS synthesis is a typical metabolic alteration in cancer, which is achieved by the upregulation of transporter proteins and various lipogenic enzymes 40,42–44 . Mammals produce only certain FASs and other FASs notably polyunsaturated FASs, are acquired from the diet by FAS protein transporters (e.g., CD36, SLC27, and plasma membrane FAS‐binding proteins [FASBPs]) 45,46 . Hydrogen sulfide, palmitic acid, and high‐FAst diet‐induced CD36 expression, which enhanced FAS uptake and cancer development 46–49 .…”
Section: Metabolism In Tumorsmentioning
confidence: 99%
“…40,[42][43][44] Mammals produce only certain FASs and other FASs notably polyunsaturated FASs, are acquired from the diet by FAS protein transporters (e.g., CD36, SLC27, and plasma membrane FAS-binding proteins [FASBPs]). 45,46 Hydrogen sulfide, palmitic acid, and high-FAst diet-induced CD36 expression, which enhanced FAS uptake and cancer development. [46][47][48][49] ATPcitrate lyase (ACLY), catalyzes the conversion of citrate and CoA to oxaloacetate and acetyl-CoA, is transcriptionally upregulated by sterol regulatory element binding protein 1 (SREBP1).…”
Metabolic dysregulation is a hallmark of cancer, underpinning diverse aggressive behaviors such as uncontrolled proliferation, immune evasion, and metastasis. Despite the potential of tumor metabolites as biomarkers, their utility has been hampered by metabolic heterogeneity. Exploring cancer metabolism aims to discern shared metabolic pathways and have a better understanding the metabolic heterogeneity of tumors. This approach offers a holistic view of cancer metabolism, facilitating the identification of multicancer‐relevant metabolic targets and the development of more broadly effective therapeutics. In this review, we present a comprehensive overview of the current landscape of cancer metabolism and its prospective applications in cancer diagnosis and prognosis. We delineate common metabolic aberrations observed across a spectrum of cancer types and elucidate the unique metabolic signatures characterizing the six leading causes of cancer‐related mortality. Furthermore, we survey the utilization of untargeted metabolomics and single‐cell technologies in cancer screening, diagnosis, and prognosis, while also spotlighting available data resources for pan‐cancer metabolomics analyses. Throughout this discussion, we tackle prevailing research challenges and propose strategies aimed at enhancing cancer management. Our objective is to furnish valuable insights that can inform and guide future research endeavors in the dynamic realm of cancer metabolism.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.