4-Methyl-2-oxopentanoic acid is an abnormal metabolite, a neurotoxin and a metabolic toxin. 4-Methyl-2-oxopentanoic acid increases endoplasmic reticulum stress, promotes lipid accumulation in preadipocytes and insulin resistance by impairing mTOR and autophagy signaling pathways[1] [2].
4-Methyl-2-oxopentanoic acid (0-300μM; 2d) treatment concentration-dependently increased lipid accumulation and the expression of lipogenic proteins, such as processed SREBP1 and SCD1, in 3T3-L1 preadipocytes[1]. 4-Methyl-2-oxopentanoic acid (1-10mM) reduced the HT-22 cells’ metabolic ability to reduce cytotoxicity and increased RS production in hippocampal neurons[2].
Mitochondrial complexes activities were reduced, and the formation of reactive species (RS) was increased in the hippocampus of rats after 4-Methyl-2-oxopentanoic acid (4mol/L, 2μL; ICV) administration[2].4-Methyl-2-oxopentanoic acid（10mmol/l; ICV） stimulated insulin secretion and elevated the NADPH/NADP+ ratio of islets preincubated in the absence of fuel[3].4-Methyl-2-oxopentanoic acid (400μmol/kg/h; carotid arch injection; single dose injection 60 min) increases porcine skeletal muscle protein synthesis and plasma leucine levels[4].
References:
[1].Park T J, Park S Y, Lee H J, et al. α-ketoisocaproic acid promotes ER stress through impairment of autophagy, thereby provoking lipid accumulation and insulin resistance in murine preadipocytes[J]. Biochemical and Biophysical Research Communications, 2022, 603: 109-115.
[2]. Farias H R, Gabriel J R, Cecconi M L, et al. The metabolic effect of α-ketoisocaproic acid: in vivo and in vitro studies[J]. Metabolic Brain Disease, 2021, 36: 185-192.
[3]. Panten U, Rustenbeck I. Fuel-induced amplification of insulin secretion in mouse pancreatic islets exposed to a high sulfonylurea concentration: role of the NADPH/NADP+ ratio[J]. Diabetologia, 2008, 51: 101-109.
[4]. Escobar J, Frank J W, Suryawan A, et al. Leucine and α-ketoisocaproic acid, but not norleucine, stimulate skeletal muscle protein synthesis in neonatal pigs[J]. The Journal of nutrition, 2010, 140(8): 1418-1424.
4-Methyl-2-oxopentanoic acid是一种异常代谢物、神经毒素和代谢毒素。4-Methyl-2-oxopentanoic acid通过损害 mTOR 和自噬信号通路，增加内质网应激，促进前脂肪细胞脂质积累和胰岛素抵抗[1][2]。
4-Methyl-2-oxopentanoic acid (0-300μM; 2d) 处理3T3-L1前脂肪细胞，以浓度依赖性增加了细胞中的脂质积累和脂肪生成蛋白（如加工的SREBP1和SCD1）表达[1]。4-Methyl-2-oxopentanoic acid（1-10mM）降低了HT-22细胞的代谢能力，从而减少了细胞毒性，并增加了海马神经元中活性物质的产生[2]。
给大鼠注射4-Methyl-2-oxopentanoic acid（4mol/L，2μL；ICV）后，大鼠海马线粒体复合物活性降低，活性物质（RS）的形成增加[2]。4-Methyl-2-oxopentanoic acid（10mmol/l；ICV） 刺激胰岛素分泌，并提高无燃料预孵育胰岛的 NADPH/NADP+ 比率[3]。4-Methyl-2-oxopentanoic acid（400μmol/kg/h；颈动脉弓注射；单剂量注射 60 分钟）可增加猪骨骼肌蛋白质合成和血浆亮氨酸水平[4]。