Using HepG2 cell, Xia et al. revealed that retinol binding protein 4 (RBP4) activated critical lipogenic transcription factors of sterol regulatory element-binding protein-1c (SREBP-1c) and liver X receptor through the stimulation of peroxisome proliferator-activated receptor-γ coactivator 1β (PGC-1β). The stimulatory effect of RBP4 on SREBP-1c activity associated with hepatic lipogenesis was ensured also in vivo. Xia et al. conclude that the activation of SREBP-1c by RBP4 is fully dependent on up-regulation of PGC-1β, because RBP4 did not exhibit lipogenic effect in PGC-1β-knockout mice. In the associated editorial, Dr. Maher raises an important question of whether RBP4 is directly linked to hepatic lipogenesis, but neither Xia et al. or Maher address the issue about the unidentified hepatic receptor of RBP4. The only known receptor for RBP4 is a receptor stimulated by retinoic acid-6 (STRA6), which is expressed in several tissues, including retina, brain, spleen, thymus, female genital tract, testis, muscle, and placental endothelial cells (and in small quantities in heart and lung), whereas STRA6 has not been identified in the liver. Until the discovery of the hepatic receptor of RBP4, the metabolic link between RBP4 and fat is not confirmed. Recently, Alapatt et al. reported that RBP4 receptor-2 (RBPR2), which is primarily expressed in the liver and intestine and induced in adipose tissue in obese mice, is likely to mediate effects of RBP4 on insulin action and glucose homeostasis in the capacity of an RBP4 receptor. To define the role of RBP4 in lipid metabolism, it would be necessary to investigate the effect of RBP4 also under the condition of knockdown of RBPR2.
PGC-1β has been thought to be a coactivator of lipogenic transcription factors, leading to lipogenesis. However, a recent study suggests that PGC-1β plays dual roles in regulating hepatic fatty acid metabolism by controlling the expression of programs of genes involved in both fatty acid oxidation and de novo fatty acid synthesis, because PGC-1β-deficient mice were outwardly normal, but exhibited a significant increase in hepatic triglyceride content at 6 weeks of age. The lipogenic effects of RBP4 shown by Xia et al. might be time-dependent.
Tetsuji Fujita, M.D.
Department of Surgery
Jikei University School of Medicine