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Alwayn et al. insightfully argue that the high value of mead acid (20:3 n-9) / arachidonic acid (20:4 n-6) ratio (M/A) in livers from our animals indicates severe deficiency in essential fatty acids, and that the model we employed is therefore close to hepatic steatosis due to essential fatty acid deficiency (EFAD). It depends on how one defines EFAD considering that M/A > 0.4 could be another criterion.1

Overall, EFAD animal models are generally made by feeding them for several weeks diets without essential fatty acids, while the duration is only one week in our protocol for ob/ob mice. In fact, according to our preliminary data, feeding with the basal fat-free diet one week was not long enough to see an appreciable increase in liver triglyceride contents in C57BL/6J mice. Besides, it has been well established that fatty livers observed in ob/ob homozygous mice are caused by increased lipogenesis mediated through sustained activation of SREBP-1c,2 which presumably originates from hyperphagia. Thus, it is unlikely that EFAD played a major role in the development of steatosis in our ob/ob model.

However, this does not exclude the possibility that SREBP-1 could be involved in the pathogenesis of steatosis associated with EFAD. Fat-free diet is a key factor for maximum dietary induction of SREBP-1c and essential fatty acids specifically suppress the expression of mature SREBP-1 protein as others and we previously showed.3 It is plausible that EFAD induces hepatic SREBP-1c, which contributes to the development of steatosis.

REFERENCES

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  • 1
    Holman RT. The ratio of trienoic : tetraenoic acids in tissue lipids as a measure of essential fatty acid requirement. J Nutr 1960; 70: 405410.
  • 2
    Yahagi N, Shimano H, Hasty AH, Matsuzaka T, Ide T, Yoshikawa T, et al. Absence of sterol regulatory element-binding protein-1 (SREBP-1) ameliorates fatty livers but not obesity or insulin resistance in Lep(ob)/Lep(ob) mice. J Biol Chem 2002; 277: 1935319357.
  • 3
    Yahagi N, Shimano H, Hasty AH, Amemiya-Kudo M, Okazaki H, Tamura Y, et al. A crucial role of sterol regulatory element-binding protein-1 in the regulation of lipogenic gene expression by polyunsaturated fatty acids. J Biol Chem 1999; 274: 3584035844.