Obesity is rising in prevalence and poses a major concern for the health of our general population. Currently affecting over one-third of the population of the United States, obesity is often comorbid with other diseases, such as diabetes, fatty liver disease, cardiovascular disease, and some cancers. The bile acid (BA)-sensing nuclear receptor Farnesoid X-Receptor (FXR) is not only a key regulator of bile acid levels, but also of energy metabolism. With these functions, FXR plays an important role in protection against bile acid-associated inflammatory liver injury and obesity-induced fatty liver disease.
Jongsook Kim Kemper, professor of molecular and integrative physiology, and colleagues studied FXR functions in two recent papers. They discovered that the activation of FXR via obeticholic acid improved the prognosis of hepatic patients, however, the dual treatment of obeticholic acid and another FXR-dependent therapeutic agent was antagonistic in nature.
In the first paper, “Defective FXR-SHP regulation in obesity aberrantly increases miR-802 expression, promoting insulin resistance and fatty liver,” the role of miR-802 in FXR action in energy metabolism and treatment of obesity-associated diabetes and fatty liver was examined. Led by senior research scientist Sunmi Seok, the research was published in Diabetes. In the second paper, “BRD4 inhibition and FXR activation, individually beneficial in cholestasis, are antagonistic in combination,” the role of BRD4 in FXR action in bile acid regulation and bile acid-associated inflammatory liver disease was examined. Led by postdoctoral researcher Hyunkyung Jung, the work was published in JCI Insight. The BRD4 studies were a collaborative effort with Lin-Feng Chen, professor of biochemistry.
Levels of some microRNA (miRs) are elevated in obesity, Kemper said. While the exact mechanism for elevated expression is unknown, the Kemper lab hypothesized defective function of FXR in obesity contributed to the upregulation of miR genes. Seok and Kemper studied the role of a nuclear receptor cascade, which involves FXR and FXR-induced Small Heterodimer Partner (SHP), in the normal regulation of miR-802 expression to maintain healthy glucose and lipid levels. However, this inhibition of miR-802 by FXR-SHP is defective in obesity, resulting in increased miR levels that contribute to insulin resistance and fatty liver. The FXR-SHP-miR-802 pathway may present novel targets for treating obesity-related diabetes and fatty liver disease.
The Kemper lab also found that in obese mice, activation of FXR via obeticholic acid (OCA) treatment reduced miR-802 levels and improved insulin resistance and fatty liver and that these effects were nullified by the overexpression of miR-802.
“Clinically, OCA is very important. Recently, the FDA approved this drug, which is a specific agonist of FXR, to treat primary biliary cholangitis, a fatal cholestatic liver disease with inflammation and fibrosis and related conditions,” Kemper said.
Relevant to the second BRD4 paper, FXR activation via obeticholic acid treatment also reduces hepatic inflammation and fibrosis in BA-associated cholestatic liver disease. The inhibition of bromodomain-containing protein-4 (BRD4) also has anti-inflammatory and anti-fibrotic effects in murine models, suggesting that combination treatment with an FXR activator and a BRD4 inhibitor would have additive beneficial effects in treating cholestatic liver disease.
To test this idea, Jung and Kemper, together with Professor Chen, studied whether the effects of OCA treatment were enhanced by inhibiting BRD4 in cholestatic liver. Treatment with either OCA or BRD4 inhibitor, JQ1, reduced inflammation along with hepatotoxicity and fibrosis, in cholestatic mice. However, to the Kemper lab’s surprise, the combined treatment did not result increased effectiveness, but in fact, canceled the beneficial effects resulting from individual treatment with each drug.
“This result was completely unanticipated, and it reminds researchers to proceed with some level of caution with respect to combination treatments,” Kemper said.
The Kemper lab’s findings on an FXR-SHP-miR-802 pathway and paradoxical effects on inflammatory liver disease by FXR and BRD4 provide interesting insights into the role of FXR in liver disease as well as potential novel anti-fibrotic and anti-inflammatory therapeutic targets.
