In previous studies it was demonstrated that sterol regulatory element-binding proteins (SREBPs) are able to interact with one of the nuclear receptors, hepatocyte nuclear receptor (HNF)-4, and that this interaction regulates transcriptional activities of these proteins (Misawa, K., Horiba, T., Arimura, N., Hirano, Y., Inoue, J., Emoto, N., Shimano, H., Shimizu, M., and Sato, R. SREBPs 3 are synthesized as membrane-bound precursor proteins and proteolytically processed to yield the N-terminal transcription factor domain that enters the nucleus. In the nucleus these transcription factors activate most genes required to produce cholesterol and fatty acids. As long as intracellular cholesterol concentrations are sufficient, SREBPs remain bound to mainly the endoplasmic reticulum (ER) as a trimer composed of SREBP, the SREBP cleavage-activating protein, and the insulin-inducing gene. Once the cholesterol contents in ER membranes decline, the SREBP⅐SREBP cleavage-activating protein complex can no longer bind to insulininducing gene, thereby exiting the ER and reaching the Golgi apparatus where the SREBPs are proteolytically processed by two Golgi-associated membrane bound proteases (1, 2).Concomitant with the well regulated proteolytic activation of SREBPs on the ER-Golgi membranes, the transcriptional activities of nuclear SREBPs are also modulated in diverse ways. We previously reported that the nuclear forms of SREBPs are rapidly degraded after being modified by polyubiquitin chains through a ubiquitin-proteasome pathway (3). The strict activation of SREBPs by the proteolytic process through monitoring the ER membrane cholesterol content becomes relevant only when the nuclear SREBPs are not retained in the nucleus for a long period. Sumoylation or phosphorylation is another type of modification of nuclear SREBPs conditioning their transcriptional activities (4 -7). Moreover, the interaction with other nuclear proteins such as the cAMP response element-binding protein (CREB) and HNF-4 can also modulate SREBP activities (8,9). Although the interaction between SREBPs and certain transcription factors is thought to exert reciprocal effects on their transcriptional activities, such cross-talk remains poorly understood.In the present study we demonstrate that LRH-1, among several nuclear receptors involved in the regulation of lipid metabolism, affects the SREBP family members' transcriptional activities. This cross-talk brings about the mutual inhibition of transcriptional activity. We demonstrate the protein interaction between LRH-1 and SREBPs and identify the interaction regions of these molecules. Based on the fact that the activities of several nuclear receptors are modulated by the small het-* This work was supported by research grants from the Ministry of Education, Science, Sports, and Culture of Japan and the program for promotion of Basic Research Activities for Innovative Biosciences. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be...