Reduction in Obesity-Related Hepatic Fibrosis by SR1664

SIMPLE SUMMARY: Obesity can contribute to the development of liver disease, including the accumulation of excess collagen (fibrosis), which leads to organ dysfunction. Drugs that target peroxisome-proliferator-activated receptor gamma (PPARγ), a protein that controls genes involved in fat storage and fibrosis, have been used to treat diabetes, but can cause unwanted side-effects. Newer drugs have been designed that selectively target PPARγ to retain the antidiabetic effects, but without the side-effects such as weight gain and bone loss, but less is known about whether they reduce fibrosis. We hypothesized that one of these new drugs (SR1664) would improve the liver fibrosis associated with obesity. We used mice fed a diet high in fat and carbohydrates to induce fatty liver with fibrosis, and then determined the effect of SR1664. We found that SR1664 did not improve insulin sensitivity, but effectively reduced liver fibrosis, without causing weight gain. These findings support the use of selective PPARγ drugs for the treatment of liver fibrosis. ABSTRACT: Peroxisome-proliferator-activated receptor gamma (PPARγ) is a transcription factor with adipogenic, insulin-sensitizing, and antifibrotic properties. Strong PPARγ activators, such as the thiazolidinediones, can induce unwanted effects such as edema, weight gain, and bone loss, and therefore selective modulators of PPARγ are in development. We previously reported that one selective PPARγ modulator, SR1664, reduced toxin-induced hepatic fibrosis and the activation of hepatic stellate cells (HSCs), the main collagen-producing liver cell in fibrosis. In this study, we used a high fat and high carbohydrate (HFHC) model of hepatic steatosis and fibrosis to determine the effect of SR1664. Mice were placed on a standard chow or HFHC diet for 16 weeks, with SR1664 or control treatment for the final 4 weeks. SR1664 did not alter weight gain or fasting insulin or glucose levels. The size of lipid droplets in the HFHC group was reduced by SR1664, but there was no effect on total liver triglyceride levels. The degree of fibrosis was significantly reduced by SR1664 in mice on the HFHC diet, and this was accompanied by a decrease in activated HSC. In summary, SR1664 improved insulin sensitivity and reduced fibrosis in the HFHC diet, suggesting selective PPARγ modulation is effective in obesity-related liver fibrosis.