5-PAHSA is an important member of the fatty acid esters of fatty acids (FAHFAs) family, a recently discovered class of endogenous lipid molecules[1]. 5-PAHSA improves glucose homeostasis and insulin sensitivity, exhibiting potent anti-diabetic and anti-inflammatory properties[2, 3]. 5-PAHSA is naturally present in human and animal adipose tissue, liver, and blood, with its levels influenced by factors such as diet, insulin sensitivity, and genetic background[4].
In vitro, 5-PAHSA (30μM) treatment of PC12 cells for 24h reduced intracellular reactive oxygen species (ROS) levels, increased C-reactive protein (CRP) levels, and induced autophagy[5]. Treatment of HepG2 and 3T3-L1 cells with 5-PAHSA (20μM) for 2 days significantly reduced insulin resistance induced by high insulin and TNF-α, improving glucose uptake and insulin signaling[6].
In vivo, oral administration of 5-PAHSA (50 or 150mg/kg/day) to db/db mice for 30 days significantly reduced serum oxidized low-density lipoprotein (ox-LDL) levels and the phosphorylation level of mTOR protein at Ser2448 in the cerebral cortex[5].
References:
[1] Aryal P, Syed I, Lee J, et al. Distinct biological activities of isomers from several families of branched fatty acid esters of hydroxy fatty acids (FAHFAs)[J]. Journal of lipid research, 2021, 62: 100108.
[2] Yore M M, Syed I, Moraes-Vieira P M, et al. Discovery of a class of endogenous mammalian lipids with anti-diabetic and anti-inflammatory effects[J]. Cell, 2014, 159(2): 318-332.
[3] Pflimlin E, Bielohuby M, Korn M, et al. Acute and repeated treatment with 5-PAHSA or 9-PAHSA isomers does not improve glucose control in mice[J]. Cell metabolism, 2018, 28(2): 217-227. e13.
[4] Kang Z, Jin Z, Wu L, et al. Investigating the Pathogenesis and Treatment of Type 2 Diabetes from the Perspective of Adipose Tissue[J]. Diabetes, Metabolic Syndrome and Obesity, 2025: 2343-2360.
[5] Wang J, Yu Z, Tao Y, et al. A novel palmitic acid hydroxy stearic acid (5‐PAHSA) plays a neuroprotective role by inhibiting phosphorylation of the m‐TOR‐ULK1 pathway and regulating autophagy[J]. CNS neuroscience & therapeutics, 2021, 27(4): 484-496.
[6] Wang Y M, Liu H X, Fang N Y. High glucose concentration impairs 5-PAHSA activity by inhibiting AMP-activated protein kinase activation and promoting nuclear factor-kappa-B-mediated inflammation[J]. Frontiers in pharmacology, 2019, 9: 1491.
5-PAHSA是一种脂肪酸脂肪酸酯（Fatty Acid Esters of Fatty Acids, FAHFAs） 家族中的重要成员，这个家族是一类新发现的内源性脂质分子[1]。5-PAHSA能够改善葡萄糖稳态和胰岛素敏感性，具有强效抗糖尿病和抗炎特性[2, 3]。5-PAHSA在人体和动物的脂肪组织、肝脏和血液中天然存在，其水平受饮食、胰岛素敏感性和遗传背景等因素影响[4]。
在体外，5-PAHSA（30µM）处理PC12细胞24h，降低了细胞内活性氧（ROS）水平，升高了C反应蛋白（CRP）水平，诱导了细胞自噬[5]。5-PAHSA（20µM）处理HepG2细胞和3T3-L1细胞2天，显著降低了高胰岛素和TNF-α诱导的胰岛素抵抗，改善了细胞的葡萄糖摄取和胰岛素信号转导[6]。
在体内，5-PAHSA（50, 150mg/kg/day）通过口服处理DB/DB小鼠30天，显著降低了小鼠血清中氧化型低密度脂蛋白（ox-LDL）的水平，也显著降低了大脑皮层中mTOR蛋白在Ser2448位点的磷酸化水平[5]。