Acetylcholinesterase (AChE) inhibition aggravates fasting-induced triglyceride accumulation in the mouse liver

Shin Ichi Yokota, Kaai Nakamura, Midori Ando, Hiroyasu Kamei, Fumihiko Hakuno, Shin Ichiro Takahashi, Shigenobu Shibata

    Research output: Contribution to journalArticle

    5 Citations (Scopus)

    Abstract

    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.

    Original languageEnglish
    Pages (from-to)905-914
    Number of pages10
    JournalFEBS Open Bio
    Volume4
    DOIs
    Publication statusPublished - 2014 Dec 1

    Fingerprint

    Acetylcholinesterase
    Liver
    Fasting
    Triglycerides
    Sterol Regulatory Element Binding Protein 1
    Fatty Acid-Binding Proteins
    Physostigmine
    Muscarinic Receptors
    Lipid Metabolism
    Insulin
    Plasmas
    Inhibition (Psychology)
    Proteins
    Lipid Metabolism Disorders
    Parasympathetic Nervous System
    Cholinesterase Inhibitors
    Cholinesterases
    Neurology
    Atropine
    Muscarinic Antagonists

    Keywords

    • Fatty liver
    • Lipogenesis
    • Lipolysis
    • Metabolic syndrome
    • Parasympathetic nerve
    • Triglyceride

    ASJC Scopus subject areas

    • Biochemistry, Genetics and Molecular Biology(all)

    Cite this

    Acetylcholinesterase (AChE) inhibition aggravates fasting-induced triglyceride accumulation in the mouse liver. / Yokota, Shin Ichi; Nakamura, Kaai; Ando, Midori; Kamei, Hiroyasu; Hakuno, Fumihiko; Takahashi, Shin Ichiro; Shibata, Shigenobu.

    In: FEBS Open Bio, Vol. 4, 01.12.2014, p. 905-914.

    Research output: Contribution to journalArticle

    Yokota, Shin Ichi ; Nakamura, Kaai ; Ando, Midori ; Kamei, Hiroyasu ; Hakuno, Fumihiko ; Takahashi, Shin Ichiro ; Shibata, Shigenobu. / Acetylcholinesterase (AChE) inhibition aggravates fasting-induced triglyceride accumulation in the mouse liver. In: FEBS Open Bio. 2014 ; Vol. 4. pp. 905-914.
    @article{9cc8d3269515461a912bed81d4468164,
    title = "Acetylcholinesterase (AChE) inhibition aggravates fasting-induced triglyceride accumulation in the mouse liver",
    abstract = "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.",
    keywords = "Fatty liver, Lipogenesis, Lipolysis, Metabolic syndrome, Parasympathetic nerve, Triglyceride",
    author = "Yokota, {Shin Ichi} and Kaai Nakamura and Midori Ando and Hiroyasu Kamei and Fumihiko Hakuno and Takahashi, {Shin Ichiro} and Shigenobu Shibata",
    year = "2014",
    month = "12",
    day = "1",
    doi = "10.1016/j.fob.2014.10.009",
    language = "English",
    volume = "4",
    pages = "905--914",
    journal = "FEBS Open Bio",
    issn = "2211-5463",
    publisher = "Elsevier BV",

    }

    TY - JOUR

    T1 - Acetylcholinesterase (AChE) inhibition aggravates fasting-induced triglyceride accumulation in the mouse liver

    AU - Yokota, Shin Ichi

    AU - Nakamura, Kaai

    AU - Ando, Midori

    AU - Kamei, Hiroyasu

    AU - Hakuno, Fumihiko

    AU - Takahashi, Shin Ichiro

    AU - Shibata, Shigenobu

    PY - 2014/12/1

    Y1 - 2014/12/1

    N2 - 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.

    AB - 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.

    KW - Fatty liver

    KW - Lipogenesis

    KW - Lipolysis

    KW - Metabolic syndrome

    KW - Parasympathetic nerve

    KW - Triglyceride

    UR - http://www.scopus.com/inward/record.url?scp=84910027830&partnerID=8YFLogxK

    UR - http://www.scopus.com/inward/citedby.url?scp=84910027830&partnerID=8YFLogxK

    U2 - 10.1016/j.fob.2014.10.009

    DO - 10.1016/j.fob.2014.10.009

    M3 - Article

    VL - 4

    SP - 905

    EP - 914

    JO - FEBS Open Bio

    JF - FEBS Open Bio

    SN - 2211-5463

    ER -