These intriguing results were confirmed in a diet-induced obesity and insulin resistance model. Liver-specific knockout of Lrh-1 had no effect on development of obesity and diabetes
when a high-fat diet was applied over 15 weeks. However, DLPC treatment substantially improved Cyclopamine research buy glucose homeostasis, and decreased hepatic glucose production, and serum glucose and insulin levels. Improved hepatic insulin sensitivity may have been caused by increased insulin-dependent phosphorylation of the insulin receptor IRS2. Despite unchanged food intake, total body weight, and liver weight, hepatic triglycerides and NEFAs were reduced following DLPC administration and mouse livers showed reduced steatosis. Mechanistically, DLPC markedly decreased expression of genes associated with de novo lipogenesis, especially the lipogenic transcription factor Srebp-1c and its key downstream targets Acc-2, Scd-1, and Fasn. However, no effects of DLPC were observed on hepatic expression of a number of genes controlling glucose homeostasis. It is noteworthy that both serum and hepatic bile salts nearly doubled following DLPC treatment, alongside an induction of Cyp7a1 and Cyp8b1 in the liver. All reported effects of DLPC
were absent when LRH-1 was conditionally deleted in the liver. DLPC thus proved to be of potential find more therapeutic benefit in both genetic and diet-induced models of insulin resistance. Encouraged by these results, Lee et al. suggest that DLPC might be a promising therapeutic agent for the treatment of metabolic MCE disorders. Consequently, the group has initiated a clinical trial to explore the effect of DLPC in prediabetic
patients. How does DLPC improve insulin sensitivity and reduce steatosis? The authors reason that the beneficial effect of DLPC on steatosis might be a result of the markedly decreased expression of Srebp-1c and/or decreased insulin levels. They propose the following regulatory loop (Fig. 1): Lrh-1-dependent repression of Srebp-1c expression may improve steatosis, increase insulin sensitivity, and hence decrease serum insulin; and decreased insulin levels in turn may reinforce repression of Srebp-1c,5 further ameliorating steatosis. This model is supported by previous data from other groups: the repression of Srebp-1c by way of Lrh-1 is consistent with a functional antagonism of SREBP-1c transactivation by LRH-16 and Srebp-1c target genes Acc-2 and Scd-1 have been shown to modulate β-oxidation, hepatic steatosis, and insulin resistance.1 Do bile salts contribute to the antidiabetic and antisteatotic effects of DLPC? Upon DLPC treatment, bile salts in serum and more strikingly in liver tissue were markedly increased. This is remarkable because hepatic bile salt levels are tightly controlled. Feeding a 1% cholate (w/w) diet only induces an increase of hepatic bile salts by approximately 50% in mice.