2. Academic Validation
  3. Fructose-1,6-bisphosphatase is a nonenzymatic safety valve that curtails AKT activation to prevent insulin hyperresponsiveness

Fructose-1,6-bisphosphatase is a nonenzymatic safety valve that curtails AKT activation to prevent insulin hyperresponsiveness

  • Cell Metab. 2023 Apr 12;S1550-4131(23)00126-2. doi: 10.1016/j.cmet.2023.03.021.
Li Gu 1,  Yahui Zhu 2,  Kosuke Watari 1,  Maiya Lee 1,  Junlai Liu 1,  Sofia Perez 1,  Melinda Thai 1,  Joshua E Mayfield 3,  Bichen Zhang 4,  Karina Cunha E Rocha 4,  Fuming Li 5,  Laura C Kim 6,  Alexander C Jones 3,  Igor H Wierzbicki 3,  Xiao Liu 7,  Alexandra C Newton 3,  Tatiana Kisseleva 8,  Jun Hee Lee 9,  Wei Ying 4,  David J Gonzalez 10,  Alan R Saltiel 4,  M Celeste Simon 6,  Michael Karin 11
Affiliations

Affiliations

  • 1 Laboratory of Gene Regulation and Signal Transduction, Departments of Pharmacology and Pathology, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
  • 2 School of Medicine, Chongqing University, Chongqing 400030, China.
  • 3 Department of Pharmacology, University of California, San Diego, La Jolla, CA 92093, USA.
  • 4 Division of Endocrinology & Metabolism, Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
  • 5 Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, PA 19104, USA; Shanghai Key Laboratory of Metabolic Remodeling and Health, Institute of Metabolism and Integrative Biology, Fudan University, Shanghai 200438, China.
  • 6 Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, PA 19104, USA.
  • 7 Division of Endocrinology & Metabolism, Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA; Department of Surgery, University of California, San Diego, La Jolla, CA 92093, USA.
  • 8 Department of Surgery, University of California, San Diego, La Jolla, CA 92093, USA.
  • 9 Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
  • 10 Department of Pharmacology, University of California, San Diego, La Jolla, CA 92093, USA; Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA, USA.
  • 11 Laboratory of Gene Regulation and Signal Transduction, Departments of Pharmacology and Pathology, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA. Electronic address: karinoffice@ucsd.edu.
PMID: 37084733 DOI: 10.1016/j.cmet.2023.03.021
Abstract

Insulin inhibits gluconeogenesis and stimulates glucose conversion to glycogen and lipids. How these activities are coordinated to prevent hypoglycemia and hepatosteatosis is unclear. Fructose-1,6-bisphosphatase (FBP1) is rate controlling for gluconeogenesis. However, inborn human FBP1 deficiency does not cause hypoglycemia unless accompanied by fasting or starvation, which also trigger paradoxical hepatomegaly, hepatosteatosis, and hyperlipidemia. Hepatocyte FBP1-ablated mice exhibit identical fasting-conditional pathologies along with Akt hyperactivation, whose inhibition reversed hepatomegaly, hepatosteatosis, and hyperlipidemia but not hypoglycemia. Surprisingly, fasting-mediated Akt hyperactivation is Insulin dependent. Independently of its catalytic activity, FBP1 prevents Insulin hyperresponsiveness by forming a stable complex with Akt, PP2A-C, and aldolase B (ALDOB), which specifically accelerates Akt dephosphorylation. Enhanced by fasting and weakened by elevated Insulin, FBP1:PP2A-C:ALDOB:AKT complex formation, which is disrupted by human FBP1 deficiency mutations or a C-terminal FBP1 truncation, prevents insulin-triggered liver pathologies and maintains lipid and glucose homeostasis. Conversely, an FBP1-derived complex disrupting peptide reverses diet-induced Insulin resistance.

Keywords

AKT; FBP1; hepatomegaly; hepatosteatosis.

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