On the other hand, they reported that increased intracellular glucose-derived metabolites inhibit enzymes for β-oxidation, leading to cytosolic accumulation of lipids [37]. Subsequently, there have been several reports about the molecular mechanism underlying glucolipotoxicity involved in pancreatic β cell dysfunction and insulin resistance [38–40]. Furthermore, phenomena of glucolipotoxicity are also observed in DN of humans [1–4] and rodents [41, 42], but their pathophysiology remains largely unknown [8]. Here,

we will compare glucolipotoxicity upon pancreatic β cell dysfunction and DN. c-Jun N-terminal kinase (JNK) JNK plays a pivotal role in ER stress-induced ‘unfolded protein response’ in innate immune system [43]. It was later revealed that ER stress-induced JNK activation is associated with chronic inflammation or high ambient fatty see more acid

levels in obesity or type 2 diabetes [44, 45]. In pancreatic β-cells, high glucose concentrations augment lipotoxicity Selleck Small molecule library through JNK activation, at least partly, in an ER stress-dependent manner [46, 47]. In our diabetic-hyperlipidemic model [5], treatment www.selleckchem.com/products/qnz-evp4593.html with STZ and HFD synergistically increases phosphorylation of IκB and mRNA expression of pro-inflammatory genes in the kidney, in parallel with phosphorylation of JNK, but not with phosphorylation of other mitogen-activated protein (MAP) kinases such as p38 or extracellular signal-regulated kinase (ERK) (Fig. 2). Fig. 2 Western blot analysis for phosphorylation of MAP kinases and IκB in kidney of STZ + HFD mice. p-/t-p38 NADPH-cytochrome-c2 reductase phosphorylated/total p38 MAP kinase, p/tERK

phosphorylated/total extracellular signal-regulated kinase, p/tJNK phosphorylated/total c-Jun N-terminal kinase, pIκB phosphorylated inhibitor of κB. Modified from Kuwabara and others [5] CCAAT element binding protein beta (C/EBPβ) CCAAT element binding protein beta (C/EBPβ) is one of the transcriptional repressors of insulin gene and induced by chronic hyperglycemia [48]. C/EBPβ is increased by fatty acids through the Per-Arnt-Sim kinase (PASK) pathway [49] in pancreatic β cells. Since PASK is also induced by high glucose conditions, these mechanisms may possibly exert glucolipotoxic effects. In the kidney, C/EBPβ is increased in diabetic rats, but not other C/EBP isoforms [50]. Furthermore, renal upregulation of C/EBPβ mRNA in STZ-induced diabetic mice is further enhanced by additional HFD feeding in our experiments [5]. Of note, JNK/AP-1 and C/EBPβ pathways may also contribute to glucolipotoxicity-induced renal damage through upregulation of myeloid-related protein 8 (MRP8, also known as S100A8 or calgranulin A), whose gene promoter region contains AP-1 binding site [51, 52] and C/EBP motif [53, 54], as discussed in the next section.