cis-4-[18F]fluoro-L-proline Molecular Imaging Experimental Liver Fibrosis

Qi Cao, Xin Lu, Babak Behnam Azad, Martin Pomper, Mark Smith, Jiang He, Liya Pi, Bin Ren, Zhekang Ying, Babak Saboury Sichani, Michael Morris, Vasken Dilsizian

Research output: Contribution to journalArticle

Abstract

Introduction: Early-stage liver fibrosis is potentially reversible, but difficult to diagnose. Clinical management would be enhanced by the development of a non-invasive imaging technique able to identify hepatic injury early, before end-stage fibrosis ensues. The analog of the amino acid proline, cis-4-[18F]fluoro-L-proline ([18F]fluoro-proline), which targets collagenogenesis in hepatic stellate cells (HSC), was used to detect fibrosis. Methods: Acute steatohepatitis was induced in experimental animals by liquid ethanol diet for 8 weeks, intra-gastric binge feedings every 10th day along with lipopolysaccharide (LPS) injection. The control animals received control diet for 8 weeks and an equivalent volume of saline on the same schedule as the acute steatohepatitis model. First, in vitro cellular experiments were carried out to assess [3H]proline uptake by HSC, hepatocytes and Kupffer cells derived from rats with acute steatohepatitis (n = 14) and controls (n = 14). Next, ex vivo liver experiments were done to investigate unlabeled proline-mediated collagen synthesis and its associated proline transporter expression in acute steatohepatitis (n = 5) and controls (n = 5). Last, in vivo dynamic and static [18F]fluoro-proline micro-PET/CT imaging was performed in animal models of acute steatohepatitis (n = 7) and control (n = 7) mice. Results: [3H]proline uptake was 5-fold higher in the HSCs of steatohepatitis rats than controls after incubation of up to 60 min. There was an excellent correlation between [3H]proline uptake and liver collagen expression (r-value > 0.90, p < 0.05). Subsequent liver tissue studies demonstrated 2–3-fold higher proline transporter expression in acute steatohepatitis animals than in controls, and proline-related collagen synthesis was blocked by this transporter inhibitor. In vivo micro-PET/CT studies with [18F]fluoro-proline showed 2–3-fold higher uptake in the livers of acute steatohepatitis mice than in controls. There was an excellent correlation between [18F]fluoro-proline uptake and liver collagen expression in the livers of acute steatohepatitis mice (r-value = 0.97, p < 0.001). Conclusion: [18F]fluoro-proline localizes in the liver and correlates with collagenogenesis in acute steatohepatitis with a signal intensity that is sufficiently high to allow imaging with micro-PET/CT. Thus, [18F]fluoro-proline could serve as a PET imaging biomarker for detecting early-stage liver fibrosis.

Original languageEnglish (US)
Article number90
JournalFrontiers in Molecular Biosciences
Volume7
DOIs
StatePublished - May 15 2020

Keywords

  • PET/CT
  • cis-4-[F]fluoro-L-proline
  • early stage alcoholic liver fibrosis
  • hepatic stellate cells
  • molecular imaging
  • steatohepatitis

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology (miscellaneous)

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    Cao, Q., Lu, X., Azad, B. B., Pomper, M., Smith, M., He, J., Pi, L., Ren, B., Ying, Z., Sichani, B. S., Morris, M., & Dilsizian, V. (2020). cis-4-[18F]fluoro-L-proline Molecular Imaging Experimental Liver Fibrosis. Frontiers in Molecular Biosciences, 7, [90]. https://doi.org/10.3389/fmolb.2020.00090