To further test the role of FGF21 in the development of alcoholic fatty liver, we created liver specific FGF21 knockout (Fgf21alb-cre) mice and liver specific FR1 knockout (Fr1alb-cre) mice and compared the effects of ethanol in these mice with the corresponding control mice, Fgf21fl/fl mice and Fr1fl/fl mice, respectively. Serum FGF21 was almost undetectable in the Fgf21alb-cre mice while it was unchanged in the Fr1alb-cre mice compared with the Fr1fl/fl mice; after ethanol feeding, the serum FGF21 was increased by 4-fold in the Fr1alb-cre mice but it was not induced in the Fgf21alb-cre mice (Fig 5A). Correspondingly, Fgf21alb-cre mice developed more severe alcoholic fatty liver than Fgf21fl/fl mice (Fig 5B, C), and liver TG accumulation was higher in Fgf21alb-cre mice than in Fgf21fl/fl mice (Fig 5D), suggesting that FGF21 plays an indispensible role in the development of alcoholic fatty liver. However, alcoholic fatty liver was comparable in the Fr1alb-cre mice and Fr1fl/fl mice, suggesting that FGF21 does not exert its effects through liver FR1.
