2. Academic Validation
  3. Geranylgeranyl Pyrophosphate Promotes Hepatic Lipid Accumulation by Prenylation of Perilipin4

Geranylgeranyl Pyrophosphate Promotes Hepatic Lipid Accumulation by Prenylation of Perilipin4

  • Cell Mol Gastroenterol Hepatol. 2025;19(9):101546. doi: 10.1016/j.jcmgh.2025.101546.
Yue Zhao 1,  Hong-Yu Nie 1,  Shan Jiang 2,  Meng-Fei Zhao 1,  Peng Sun 3,  Jing-Zi Zhang 1,  Xiao-Chen Wang 1,  Yi-Ping Tang 1,  Ming-Jie Zou 1,  Xian-Wen Yuan 4,  Xi-Tai Sun 4,  Xiao-Dong Shan 4,  Jian He 5,  Jiang-Huai Liu 1,  Yan Bi 1,  Lei Fang 6,  Xiao Han 7,  Chao-Jun Li 8
Affiliations

Affiliations

  • 1 The State Key Laboratory of Pharmaceutical Biotechnology and Jiangsu Key Laboratory of Molecular Medicine, Division of Immunology, Department of Endocrinology, Drum Tower Hospital Affiliated to Nanjing University Medical School, Medical School of Nanjing University, Nanjing, Jiangsu Province, China.
  • 2 State Key Laboratory of Reproductive Medicine and China International Joint Research Center on Environment and Human Health, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China.
  • 3 Key Laboratory of Human Functional Genomics of Jiangsu Province, Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing, China.
  • 4 Department of Hepatobiliary Surgery, Affiliated Drum Tower Hospital, Medical School of Nanjing University, Nanjing, China.
  • 5 Department of Nuclear Medicine, Affiliated Drum Tower Hospital, Medical School of Nanjing University, Nanjing, China.
  • 6 The State Key Laboratory of Pharmaceutical Biotechnology and Jiangsu Key Laboratory of Molecular Medicine, Division of Immunology, Department of Endocrinology, Drum Tower Hospital Affiliated to Nanjing University Medical School, Medical School of Nanjing University, Nanjing, Jiangsu Province, China. Electronic address: [email protected].
  • 7 Key Laboratory of Human Functional Genomics of Jiangsu Province, Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing, China. Electronic address: [email protected].
  • 8 State Key Laboratory of Reproductive Medicine and China International Joint Research Center on Environment and Human Health, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China. Electronic address: [email protected].
PMID: 40449844 DOI: 10.1016/j.jcmgh.2025.101546
Abstract

Background & aims: Metabolically unhealthy obesity (MUO) is characterized by hepatic steatosis and type 2 diabetes (T2D), distinct from metabolically healthy obesity (MHO). This study aimed to identify the key regulator responsible for MUO.

Methods: Metabolomics analysis was conducted to compare hepatic metabolite profiles between individuals with MUO and MHO and mice. Geranylgeranyl pyrophosphate (GGPP) levels and its synthetase geranylgeranyl diphosphate synthase (GGPPS) were quantified in human and murine liver tissues. Hepatocyte-specific Ggpps knockout mice (LKO) were generated to evaluate the effects of GGPP deficiency on MUO-associated phenotypes. Mechanistic studies focused on GGPP-dependent prenylation of the lipid droplet-associated protein Perilipin4 and its role in lipid droplet formation. The therapeutic potential of DGBP, a GGPPS inhibitor, was also tested in MUO models.

Results: GGPP and GGPPS protein expression were significantly elevated in the livers of patients with MUO and mice compared with counterparts with MHO. Hepatocyte-specific Ggpps knockout (LKO) mice exhibited reduced hepatic lipid accumulation, smaller lipid droplets, and improved Insulin sensitivity, demonstrating GGPP's critical role in MUO pathogenesis. Mechanistically, GGPP promoted Perilipin4 prenylation, which enhanced large lipid droplet formation and exacerbated hepatic steatosis and Insulin resistance. Pharmacologic inhibition of GGPPS with DGBP effectively attenuated MUO phenotypes, highlighting its therapeutic potential.

Conclusions: Hepatic GGPP drives MUO progression by facilitating Perilipin4 prenylation, thereby promoting pathological lipid droplet expansion and Insulin resistance. Targeting GGPP with inhibitors of GGPPS like DGBP represents a promising strategy for treating MUO. These findings provide novel insights into the metabolic heterogeneity of obesity and potential therapeutic interventions for MUO-related complications.

Keywords

DGBP; Geranylgeranyl Pyrophosphate (GGPP); Metabolically Healthy Obesity; Metabolically Unhealthy Obesity; Perilipin4.

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