Absence of hepatic stellate cell retinoid lipid droplets does not enhance hepatic fibrosis but decreases hepatic carcinogenesis
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Absence of hepatic stellate cell retinoid lipid droplets does not enhance hepatic fibrosis but decreases hepatic carcinogenesis. / Kluwe, Johannes; Wongsiriroj, Nuttaporn; Troeger, Juliane S; Gwak, Geum-Youn; Dapito, Dianne H; Pradere, Jean-Philippe; Jiang, Hongfeng; Siddiqi, Maham; Piantedosi, Roseann; O'Byrne, Sheila M; Blaner, William S; Schwabe, Robert F.
In: GUT, Vol. 60, No. 9, 09.2011, p. 1260-8.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Absence of hepatic stellate cell retinoid lipid droplets does not enhance hepatic fibrosis but decreases hepatic carcinogenesis
AU - Kluwe, Johannes
AU - Wongsiriroj, Nuttaporn
AU - Troeger, Juliane S
AU - Gwak, Geum-Youn
AU - Dapito, Dianne H
AU - Pradere, Jean-Philippe
AU - Jiang, Hongfeng
AU - Siddiqi, Maham
AU - Piantedosi, Roseann
AU - O'Byrne, Sheila M
AU - Blaner, William S
AU - Schwabe, Robert F
PY - 2011/9
Y1 - 2011/9
N2 - 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.
AB - 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.
KW - Acyltransferases
KW - Animals
KW - Carbon Tetrachloride
KW - Cell Transformation, Neoplastic
KW - Cells, Cultured
KW - Diethylnitrosamine
KW - Down-Regulation
KW - Hepatic Stellate Cells
KW - Liver Cirrhosis
KW - Liver Neoplasms, Experimental
KW - Male
KW - Mice
KW - Mice, Inbred C57BL
U2 - 10.1136/gut.2010.209551
DO - 10.1136/gut.2010.209551
M3 - SCORING: Journal article
C2 - 21278145
VL - 60
SP - 1260
EP - 1268
JO - GUT
JF - GUT
SN - 0017-5749
IS - 9
ER -