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Reduction in Obesity-Related Hepatic Fibrosis by SR1664
Benita L McVicker1,2, Ronda L Simpson1,2, Frederick G Hamel1,3
1Research Service, Nebraska-Western Iowa Health Care System, Omaha, NE 68105, USA.
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.
Insights
Selective PPARγ modulator SR1664 reduced liver fibrosis and improved insulin sensitivity in mice on a high-fat, high-carbohydrate diet. This suggests targeted PPARγ modulation may treat obesity-related liver disease.
Area of Science:
- Pharmacology
- Hepatology
- Metabolic Diseases
Background:
- Peroxisome-proliferator-activated receptor gamma (PPARγ) influences fat metabolism and insulin sensitivity.
- While potent PPARγ activators cause side effects, selective modulators like SR1664 are being developed.
- Previous studies showed SR1664 reduced toxin-induced liver fibrosis.
Purpose of the Study:
- To investigate the efficacy of SR1664 in a high-fat, high-carbohydrate (HFHC) diet model of liver steatosis and fibrosis.
- To assess SR1664's impact on metabolic parameters and liver pathology in this model.
Main Methods:
- Mice were fed a standard or HFHC diet for 16 weeks, with SR1664 or control treatment during the final 4 weeks.
- Evaluated weight gain, fasting glucose and insulin levels, liver triglyceride content, and lipid droplet size.
- Assessed liver fibrosis and hepatic stellate cell (HSC) activation.
Main Results:
- SR1664 did not affect weight gain or fasting glucose/insulin levels.
- SR1664 reduced lipid droplet size but not total liver triglycerides in HFHC mice.
- Significant reduction in liver fibrosis and activated HSCs was observed with SR1664 treatment in HFHC mice.
Conclusions:
- SR1664 demonstrated effectiveness in reducing liver fibrosis and improving insulin sensitivity in an obesity-related liver disease model.
- Selective PPARγ modulation with SR1664 presents a potential therapeutic strategy for non-alcoholic fatty liver disease (NAFLD) and associated fibrosis.
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