The Role of Elevated Liver-Type Fatty Acid-Binding Proteins in Liver Diseases

Abstract

Liver-type fatty acid–binding protein (L-FABP) is mainly expressed in the liver as well as the proximal tubular epithelial cells in the kidney. In general, the proteins and enzymes existing within the hepatocytes have the potential to become biomarkers, for instance alanine aminotransferase, which reflects hepatocellular damage. However, due to reduced hepatocellular function in late stage of chronic liver diseases (e.g. cirrhosis), proteins and enzymes relating to hepatocellular damage are not always accurate measures of disease progression. Recently, several publications have demonstrated elevated serum L-FABP levels during the progression of human liver diseases, including hepatocellular carcinoma (HCC), and were a prognostic factor for survival in acute and chronic liver disease patients. However, the study regarding serum L-FABP levels and hepatic L-FABP expression in liver diseases is not sufficient to understand the molecular mechanism of L-FABP during the progression of these disease states. In this review, we focus on the use of serum and/or hepatic L-FABP expression as a biomarker in human liver diseases, including mechanistic potential in HCC.

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Abbreviations

ALT:

Alanine aminotransferase

ALBI:

Albumin-bilirubin

AUC:

Area under the curve

HBV:

Hepatitis B virus

HCV:

Hepatitis C virus

HCC:

Hepatocellular carcinoma

CH:

Chronic hepatitis

LC:

Liver cirrhosis

L-FABP:

Liver-type fatty acid–binding protein

HSC:

Hepatic stellate cell

KC:

Kupffer cell

AKI:

Acute kidney injury

LSEC:

Liver sinusoidal endothelial cell

CPS:

Child-Pugh scores

MELD:

Model for End-Stage Liver Disease

NASH:

Nonalcoholic steatohepatitis

ROC:

Receiver operating characteristic

BCLC:

Barcelona-Clinic Liver Cancer.

References

  1. 1.

    Trefts E, Gannon M, Wasserman DH. The liver. Curr Biol. 2017;27(21):R1147–R51.

    CAS  Article  Google Scholar 

  2. 2.

    Eguchi A, Kostallari E, Feldstein AE, Shah VH. Extracellular vesicles, the liquid biopsy of the future. J Hepatol. 2019;70(6):1292–4.

    Article  Google Scholar 

  3. 3.

    Schuster S, Cabrera D, Arrese M, Feldstein AE. Triggering and resolution of inflammation in NASH. Nat Rev Gastroenterol Hepatol. 2018;15(6):349–64.

    CAS  Article  Google Scholar 

  4. 4.

    An P, Wei LL, Zhao S, Sverdlov DY, Vaid KA, Miyamoto M, et al. Hepatocyte mitochondria-derived danger signals directly activate hepatic stellate cells and drive progression of liver fibrosis. Nat Commun. 2020;11(1):2362.

    CAS  Article  Google Scholar 

  5. 5.

    D'Amico G, Garcia-Tsao G, Pagliaro L. Natural history and prognostic indicators of survival in cirrhosis: a systematic review of 118 studies. J Hepatol. 2006;44(1):217–31.

    Article  Google Scholar 

  6. 6.

    Kamath PS, Kim WR, and Advanced Liver Disease Study G. The model for end-stage liver disease (MELD). Hepatology. 2007;45(3):797–805.

    Article  Google Scholar 

  7. 7.

    Johnson PJ, Berhane S, Kagebayashi C, Satomura S, Teng M, Reeves HL, et al. Assessment of liver function in patients with hepatocellular carcinoma: a new evidence-based approach-the ALBI grade. J Clin Oncol. 2015;33(6):550–8.

    Article  Google Scholar 

  8. 8.

    Marrero JA, Kulik LM, Sirlin CB, Zhu AX, Finn RS, Abecassis MM, et al. Diagnosis, staging, and Management of Hepatocellular Carcinoma: 2018 practice guidance by the American Association for the Study of Liver Diseases. Hepatology. 2018;68(2):723–50.

    Article  Google Scholar 

  9. 9.

    Wang YY, Zhong JH, Su ZY, Huang JF, Lu SD, Xiang BD, et al. Albumin-bilirubin versus child-Pugh score as a predictor of outcome after liver resection for hepatocellular carcinoma. Br J Surg. 2016;103(6):725–34.

    CAS  Article  Google Scholar 

  10. 10.

    Pinato DJ, Sharma R, Allara E, Yen C, Arizumi T, Kubota K, et al. The ALBI grade provides objective hepatic reserve estimation across each BCLC stage of hepatocellular carcinoma. J Hepatol. 2017;66(2):338–46.

    Article  Google Scholar 

  11. 11.

    Kuboki S, Shimizu H, Mitsuhashi N, Kusashio K, Kimura F, Yoshidome H, et al. Angiopoietin-2 levels in the hepatic vein as a useful predictor of tumor invasiveness and prognosis in human hepatocellular carcinoma. J Gastroenterol Hepatol. 2008;23(7 Pt 2):e157–64.

    CAS  Article  Google Scholar 

  12. 12.

    Torimura T, Sata M, Ueno T, Kin M, Tsuji R, Suzaku K, et al. Increased expression of vascular endothelial growth factor is associated with tumor progression in hepatocellular carcinoma. Hum Pathol. 1998;29(9):986–91.

    CAS  Article  Google Scholar 

  13. 13.

    Mikus M, Drobin K, Gry M, Bachmann J, Lindberg J, Yimer G, et al. Elevated levels of circulating CDH5 and FABP1 in association with human drug-induced liver injury. Liver Int. 2017;37(1):132–40.

    CAS  Article  Google Scholar 

  14. 14.

    Kamijo-Ikemori A, Sugaya T, Ichikawa D, Hoshino S, Matsui K, Yokoyama T, et al. Urinary liver type fatty acid binding protein in diabetic nephropathy. Clinica Chimica Acta. 2013;424:104–8.

    CAS  Article  Google Scholar 

  15. 15.

    Noiri E, Doi K, Negishi K, Tanaka T, Hamasaki Y, Fujita T, et al. Urinary fatty acid-binding protein 1: an early predictive biomarker of kidney injury. Am J Physiol Renal Physiol. 2009;296(4):F669–79.

    CAS  Article  Google Scholar 

  16. 16.

    Kamijo A, Sugaya T, Hikawa A, Yamanouchi M, Hirata Y, Ishimitsu T, et al. Urinary liver-type fatty acid binding protein as a useful biomarker in chronic kidney disease. Mol Cell Biochem. 2006;284(1–2):175–82.

    CAS  Article  Google Scholar 

  17. 17.

    Yamamoto T, Noiri E, Ono Y, Doi K, Negishi K, Kamijo A, et al. Renal L-type fatty acid--binding protein in acute ischemic injury. J Am Soc Nephrol. 2007;18(11):2894–902.

    CAS  Article  Google Scholar 

  18. 18.

    Kaikaus RM, Sui Z, Lysenko N, Wu NY, Ortiz de Montellano PR, Ockner RK, et al. Regulation of pathways of extramitochondrial fatty acid oxidation and liver fatty acid-binding protein by long-chain monocarboxylic fatty acids in hepatocytes. Effect of inhibition of carnitine palmitoyltransferase I. J Biol Chem. 1993;268(36):26866–71.

    CAS  Article  Google Scholar 

  19. 19.

    Yang X, Zhang B, Lu X, Yan M, Wen Y, Zhao T, et al. Effects of Tangshen formula on urinary and plasma liver-type fatty acid binding protein levels in patients with type 2 diabetic kidney disease: post-hoc findings from a multi-center, randomized, double-blind, placebo-controlled trial investigating the efficacy and safety of Tangshen formula in patients with type 2 diabetic kidney disease. BMC Complement Altern Med. 2016;16:246.

    Article  Google Scholar 

  20. 20.

    van den Broek MA, Bloemen JG, Dello SA, van de Poll MC, Olde Damink SW, Dejong CH. Randomized controlled trial analyzing the effect of 15 or 30 min intermittent Pringle maneuver on hepatocellular damage during liver surgery. J Hepatol. 2011;55(2):337–45.

    Article  Google Scholar 

  21. 21.

    Monbaliu D, de Vries B, Crabbe T, van Heurn E, Verwaest C, Roskams T, et al. Liver fatty acid-binding protein: an early and sensitive plasma marker of hepatocellular damage and a reliable predictor of graft viability after liver transplantation from non-heart-beating donors. Transplant Proc. 2005;37(1):413–6.

    CAS  Article  Google Scholar 

  22. 22.

    Stravitz RT, Lee WM. Acute liver failure. Lancet. 2019;394(10201):869–81.

    CAS  Article  Google Scholar 

  23. 23.

    Karvellas CJ, Speiser JL, Tremblay M, Lee WM, Rose CF, Group USALFS. Elevated FABP1 serum levels are associated with poorer survival in acetaminophen-induced acute liver failure. Hepatology. 2017;65(3):938–49.

    CAS  Article  Google Scholar 

  24. 24.

    Karvellas CJ, Speiser JL, Tremblay M, Lee WM, Rose CF, Group USALFS. Elevated Serum Liver-Type Fatty Acid Binding Protein Levels in Non-acetaminophen Acute Liver Failure Patients with Organ Dysfunction. Dig Dis Sci. 2021;66(1):273–83.

  25. 25.

    Church RJ, Kullak-Ublick GA, Aubrecht J, Bonkovsky HL, Chalasani N, Fontana RJ, et al. Candidate biomarkers for the diagnosis and prognosis of drug-induced liver injury: An international collaborative effort. Hepatology. 2019;69(2):760–73.

    CAS  Article  Google Scholar 

  26. 26.

    Lu YC, Chang CC, Wang CP, Hung WC, Tsai IT, Tang WH, et al. Circulating fatty acid-binding protein 1 (FABP1) and nonalcoholic fatty liver disease in patients with type 2 diabetes mellitus. Int J Med Sci. 2020;17(2):182–90.

    CAS  Article  Google Scholar 

  27. 27.

    Akbal E, Koçak E, Akyürek Ö, Köklü S, Batgi H, Şenes M. Liver fatty acid-binding protein as a diagnostic marker for non-alcoholic fatty liver disease. Wien Klin Wochenschr. 2016;128(1–2):48–52.

    CAS  Article  Google Scholar 

  28. 28.

    Ozenirler S, Degertekin CK, Erkan G, Elbeg S, Tuncer C, Kandilc U, et al. Serum liver fatty acid binding protein shows good correlation with liver histology in NASH. Hepato-gastroenterology. 2013;60(125):1095–100.

    CAS  PubMed  Google Scholar 

  29. 29.

    Akbal E, Koklu S, Kocak E, Cakal B, Gunes F, Basar O, et al. Liver fatty acid-binding protein is a diagnostic marker to detect liver injury due to chronic hepatitis C infection. Arch Med Res. 2013;44(1):34–8.

    CAS  Article  Google Scholar 

  30. 30.

    Pawlak M, Lefebvre P, Staels B. Molecular mechanism of PPARalpha action and its impact on lipid metabolism, inflammation and fibrosis in non-alcoholic fatty liver disease. J Hepatol. 2015;62(3):720–33.

    CAS  Article  Google Scholar 

  31. 31.

    Newberry EP, Kennedy SM, Xie Y, Luo J, Crooke RM, Graham MJ, et al. Decreased body weight and hepatic steatosis with altered fatty acid ethanolamide metabolism in aged L-Fabp −/− mice. J Lipid Res. 2012;53(4):744–54.

    CAS  Article  Google Scholar 

  32. 32.

    Chen A, Tang Y, Davis V, Hsu FF, Kennedy SM, Song H, et al. Liver fatty acid binding protein (L-Fabp) modulates murine stellate cell activation and diet-induced nonalcoholic fatty liver disease. Hepatology. 2013;57(6):2202–12.

    CAS  Article  Google Scholar 

  33. 33.

    Lin J, Zheng S, Attie AD, Keller MP, Bernlohr DA, Blaner WS, et al. Perilipin 5 and liver fatty acid binding protein function to restore quiescence in mouse hepatic stellate cells. J Lipid Res. 2018;59(3):416–28.

    CAS  Article  Google Scholar 

  34. 34.

    Ku CY, Liu YH, Lin HY, Lu SC, Lin JY. Liver fatty acid-binding protein (L-FABP) promotes cellular angiogenesis and migration in hepatocellular carcinoma. Oncotarget. 2016;7(14):18229–46.

    Article  Google Scholar 

  35. 35.

    Eguchi A, Hasegawa H, Iwasa M, Tamai Y, Ohata K, Oikawa T, et al. Serum liver-type fatty acid-binding protein is a possible prognostic factor in human chronic liver diseases from chronic hepatitis to liver cirrhosis and hepatocellular carcinoma. Hepatol Commun. 2019;3(6):825–37.

    CAS  Article  Google Scholar 

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Correspondence to Akiko Eguchi.

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Eguchi, A., Iwasa, M. The Role of Elevated Liver-Type Fatty Acid-Binding Proteins in Liver Diseases. Pharm Res 38, 89–95 (2021). https://doi.org/10.1007/s11095-021-02998-x

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Keywords

  • Liver-type fatty acid–binding protein (L-FABP)
  • acute liver disease
  • chronic liver disease
  • prognostic factor for survival
  • HCC
  • renal function