Acetylcholinesterase (AChE) inhibition aggravates fasting-induced triglyceride accumulation in the mouse liver.
Although fasting induces hepatic triglyceride (TG) accumulation in both rodents and humans, little is known about the underlying mechanism. Because parasympathetic nervous system activity tends to attenuate the secretion of very-low-density-lipoprotein-triglyceride (VLDL-TG) and increase TG stores in the liver, and serum cholinesterase activity is elevated in fatty liver disease, the inhibition of the parasympathetic neurotransmitter acetylcholinesterase (AChE) may have some influence on hepatic lipid metabolism. To assess the influence of AChE inhibition on lipid metabolism, the effect of physostigmine, an AChE inhibitor, on fasting-induced increase in liver TG was investigated in mice. In comparison with ad libitum-fed mice, 30 h fasting increased liver TG accumulation accompanied by a downregulation of sterol regulatory element-binding protein 1 (SREBP-1) and liver-fatty acid binding-protein (L-FABP). Physostigmine promoted the 30 h fasting-induced increase in liver TG levels in a dose-dependent manner, accompanied by a significant fall in plasma insulin levels, without a fall in plasma TG. Furthermore, physostigmine significantly attenuated the fasting-induced decrease of both mRNA and protein levels of SREBP-1 and L-FABP, and increased IRS-2 protein levels in the liver. The muscarinic receptor antagonist atropine blocked these effects of physostigmine on liver TG, serum insulin, and hepatic protein levels of SREBP-1 and L-FABP. These results demonstrate that AChE inhibition facilitated fasting-induced TG accumulation with up regulation of the hepatic L-FABP and SREBP-1 in mice, at least in part via the activation of muscarinic acetylcholine receptors. Our studies highlight the crucial role of parasympathetic regulation in fasting-induced TG accumulation, and may be an important source of information on the mechanism of hepatic disorders of lipid metabolism.
Department of Physiology and Pharmacology, School of Advanced Science and Engineering, Waseda University, Tokyo, Japan ; Consolidated Research Institute for Advanced Science and Medical Care, Waseda University, Tokyo, Japan.
Shin-Ichi
S
Yokota
Department of Physiology and Pharmacology, School of Advanced Science and Engineering, Waseda University, Tokyo, Japan.
Kaai
K
Nakamura
Department of Physiology and Pharmacology, School of Advanced Science and Engineering, Waseda University, Tokyo, Japan.
Midori
M
Ando
Department of Animal Sciences and Applied Biological Sciences, Graduate School of Agriculture and Life Sciences, The University of Tokyo, Tokyo, Japan.
Hiroyasu
H
Kamei
Department of Animal Sciences and Applied Biological Sciences, Graduate School of Agriculture and Life Sciences, The University of Tokyo, Tokyo, Japan.
Fumihiko
F
Hakuno
Department of Animal Sciences and Applied Biological Sciences, Graduate School of Agriculture and Life Sciences, The University of Tokyo, Tokyo, Japan.
Shin-Ichiro
S
Takahashi
Department of Physiology and Pharmacology, School of Advanced Science and Engineering, Waseda University, Tokyo, Japan.
Shigenobu
S
Shibata
ACC, acetyl coenzyme-A carboxylase; ACh, acetylcholine; AChE, acetylcholinesterase; CPT-1, carnitine palmitoyltransferase 1; FA, fatty acid(s); FAS, fatty acid synthase; Fatty liver; IRS-2, insulin receptor substrate; L-FABP, liver fatty acid-binding protein; Lipogenesis; Lipolysis; Metabolic syndrome; PEPCK, phosphoenolpyruvate carboxykinase; PGC-1α, peroxisome proliferator activated receptor gamma coactivator 1-alpha; PPAR-α, peroxisome proliferator activated receptor alpha; Parasympathetic nerve; SREBP, sterol regulatory element binding proteins; TG, triglyceride(s); Triglyceride; VLDL, very low-density lipoprotein(s)