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Absence of hepatic stellate cell retinoid lipid droplets does not enhance hepatic fibrosis but decreases hepatic carcinogenesis
  1. Johannes Kluwe1,3,
  2. Nuttaporn Wongsiriroj2,
  3. Juliane S Troeger1,
  4. Geum-Youn Gwak1,
  5. Dianne H Dapito2,
  6. Jean-Philippe Pradere1,
  7. Hongfeng Jiang1,
  8. Maham Siddiqi1,
  9. Roseann Piantedosi2,
  10. Sheila M O'Byrne2,
  11. William S Blaner1,2,
  12. Robert F Schwabe1,2
  1. 1Department of Medicine, Columbia University, College of Physicians and Surgeons, New York, New York, USA
  2. 2The Institute of Human Nutrition, Columbia University, College of Physicians and Surgeons, New York, New York, USA
  3. 3Department of Medicine, University Medical Center Hamburg-Eppendorf, Germany
  1. Correspondence to Robert F Schwabe, Russ Berrie Pavilion, Room 415, 1150 St Nicholas Ave, New York, NY 10032, USA; rfs2102{at}


Objective Hepatic stellate cells (HSCs) contain a number of bioactive metabolites or their precursors including retinoids in their characteristic lipid droplets. The loss of lipid droplets and retinoids is a hallmark of HSC activation, but it remains unclear whether this loss promotes HSC activation, liver fibrogenesis or carcinogenesis.

Design Spontaneous and experimental fibrogenesis as well as a diethylnitrosamine-induced hepatocarcinogenesis were investigated in lecithin-retinol acyltransferase (LRAT)-deficient mice which lack retinoid-containing lipids droplets in their HSCs.

Results Following HSC activation, LRAT expression was rapidly lost, emphasising its importance in lipid droplet biology in HSCs. Surprisingly, there was no difference in fibrosis induced by bile duct ligation (BDL) or by eight injections of carbon tetrachloride (CCl4) between wild-type and LRAT-deficient mice. To exclude the possibility that the effects on fibrogenesis were missed due to the rapid downregulation of LRAT following HSC activation, acute as well as spontaneous liver fibrosis was investigated. However, there was no increased fibrosis in 3-, 8- and 12-month-old LRAT-deficient mice and in LRAT-deficient mice after a single injection of CCl4 compared with wild-type mice. To determine whether the absence of retinoids in HSCs affects hepatocarcinogenesis, wild-type and LRAT-deficient mice were injected with diethylnitrosamine. LRAT deficiency decreased diethylnitrosamine-induced injury and tumour load and increased the expression of the retinoic acid responsive genes Cyp26a1, RARb and p21, suggesting that the lower tumour load of LRAT-deficient mice was a result of increased retinoid signalling and subsequent p21-mediated inhibition of proliferation.

Conclusions The absence of retinoid-containing HSC lipid droplets does not promote HSC activation but reduces hepatocarcinogenesis.

  • Liver fibrosis
  • bile duct ligation
  • carbontetrachloride
  • liver cancer
  • fibrogenesis
  • hepatic stellate cell
  • hepatocellular carcinoma

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  • Funding This study was supported by grants U54CA126513 (PI of Project 2: RFS), R01DK076920 (to RFS), R01DK709221 (to WSB) and the 2008 Charles Trey, MD Memorial Postdoctoral Research Fellowship from the American Liver Foundation (to JK).

  • Competing interests None.

  • Provenance and peer review Not commissioned; externally peer reviewed.