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    • Lipotoxicity is the accumulation of excess lipids in non adi

    2024-03-21

    Lipotoxicity is the accumulation of excess lipids in non-adipose tissues that leads to cell dysfunction or cell death. It may play an important role in the pathogenesis of diabetes, and contributes to the rate of progression of CKD [7,8]. Emerging evidence indicates that renal lipid dysregulation is a major inciting factor in the development of CKD, along with diabetic nephropathy [29,30]. When this capacity is exceeded, resultant cellular dysfunction or cell apoptosis is incited by lipotoxicity and lipoapoptosis [31]. Of the lipids that accrue, sphingolipids, including ceramides, are particularly detrimental to tissue [13,18]. Ceramides can be synthesized through three different pathways: de novo biosynthesis, the sphingomyelinase pathway, and the salvage pathway [18,32]. In the reverse direction, breakdown of ceramides is initiated by sphingosine 1-phosphate receptor modulator ceramidases, which are categorized by homology and pH at which they can hydrolyze ceramides into sphingosines and NEFAs [[32], [33], [34]]. Ceramides inhibit insulin signaling to Akt through parallel pathways involving PP2A and the protein kinase Czeta [18]. Furthermore, ceramide specifically activates a mitochondrial PP2A, which rapidly and completely induces the dephosphorylation and inactivation of Akt and Bcl-2, which are fundamental to controlling survival and apoptosis [[35], [36], [37], [38], [39], [40]]. Moreover, increased ceramide is accompanied by positive regulation of iNOS, thereby enhancing formation of nitric oxide and peroxynitrite, which induce apoptosis [41]. A potentially important influence on the vulnerability of a cell to noxious lipid derivatives may be the balance of apoptotic and anti-apoptotic members of the Bcl-2 family. Lipotoxicity or lipoapoptosis is prevented or ameliorated by eliminating superfluous lipid, or by blocking the formation of potentially harmful fatty acid derivatives, such as ceramide and ROS [31,42]. Our study showed that AdipoRon prevents and ameliorates oxidative stress-induced apoptosis in the kidney including both GECs and podocytes. AMPK has emerged as a critical mechanism for salutary effects on lipid metabolic disorders in diabetes [43]. AMPK stimulates Ser372 phosphorylation, suppresses SREBP-1c cleavage and nuclear translocation, and represses SREBP-1c target gene expression in hepatocytes exposed to high glucose, leading to reduced lipogenesis and lipid accumulation [43]. In addition, AMPK inhibits lipogenesis and enhances fatty acid oxidation through targets such as ACC and fatty acid synthase [44]. Furthermore, Liangpunsakul et al. reported that the inhibitory effect of ethanol on AMPK phosphorylation was mediated partly through increasing the levels of ceramide and activation of PP2A [45]. In addition, PPARα activated by PPARα agonist prevents and ameliorates lipotoxicity-induced renal injury by enhancing the production of lipolytic enzymes and reducing lipid accumulation, oxidative stress, and renal cell apoptosis, thereby inhibiting the development of albuminuria and glomerular fibrosis [4,22,26,46]. Adiponectin, an adipose tissue-derived cytokine, is another AMPK activator. A decrease in the plasma level of adiponectin has been correlated with insulin resistance and obesity. Furthermore, adiponectin knockout mice exhibit increased albuminuria and fusion of the podocyte foot process [47]. This insulin sensitizing effect of adiponectin seems to be mediated, at least in part, by an increase in fatty-acid oxidation via not only activation of AMPK but also via PPARα [23,48,49]. However, in this study AdipoRon treatment did not affect the serum level of adiponectin in db/db mice; therefore, we can rule out the systemic effects of AdipoRon related to the adiponectin. In the current study, we found that AdipoRon clearly increased the expressions of AdipoR1 and AdipoR2 in diabetic kidneys without an increase in systemic adiponectin levels. It has not yet been determined whether the expressions of AdipoR1 and AdipoR2 are altered with AdipoRon treatment. In the previous article, the expression of AdipoR1 and AdipoR2 appears to be inversely correlated with plasma insulin levels in vivo [50]. They suggested that down-regulation of AdipoR1 and AdipoR2 by insulin is mediated via the phosphoinositide-3-kinase/Foxo1-dependent pathway. Subsequent research showed that AdipoRon improves metabolism in the liver, skeletal muscle and adipose tissue, and ameliorates insulin resistance, diabetes and dyslipidemia in db/db mice [22]. In the current study, we also demonstrated that AdipoRon treatment decreased plasma insulin levels and dyslipidemia in db/db mice. Therefore, the decreased plasma insulin levels might have an important role to increase the expression of AdipoR1 and AdiopR2 in the kidneys in AdipoRon-fed db/db mice.