The Selective Peroxisome Proliferator‐Activated Receptor Gamma Modulator CHS‐131 Improves Liver Histopathology and Metabolism in a Mouse Model of Obesity and Nonalcoholic Steatohepatitis

Abstract

CHS‐131 is a selective peroxisome proliferator‐activated receptor gamma modulator with antidiabetic effects and less fluid retention and weight gain compared to thiazolidinediones in phase II clinical trials. We investigated the effects of CHS‐131 on metabolic parameters and liver histopathology in a diet‐induced obese (DIO) and biopsy‐confirmed mouse model of nonalcoholic steatohepatitis (NASH). Male C57BL/6JRj mice were fed the amylin liver NASH diet (40% fat with trans‐fat, 20% fructose, and 2% cholesterol). After 36 weeks, only animals with biopsy‐confirmed steatosis and fibrosis were included and stratified into treatment groups (n = 12‐13) to receive for the next 12 weeks (1) low‐dose CHS‐131 (10 mg/kg), (2) high‐dose CHS‐131 (30 mg/kg), or (3) vehicle. Metabolic parameters, liver pathology, metabolomics/lipidomics, markers of liver function and liver, and subcutaneous and visceral adipose tissue gene expression profiles were assessed. CHS‐131 did not affect body weight, fat mass, lean mass, water mass, or food intake in DIO‐NASH mice with fibrosis. CHS‐131 improved fasting insulin levels and insulin sensitivity as assessed by the intraperitoneal insulin tolerance test. CHS‐131 improved total plasma cholesterol, triglycerides, alanine aminotransferase, and aspartate aminotransferase and increased plasma adiponectin levels. CHS‐131 (high dose) improved liver histology and markers of hepatic fibrosis. DIO‐NASH mice treated with CHS‐131 demonstrated a hepatic shift to diacylglycerols and triacylglycerols with a lower number of carbons, increased expression of genes stimulating fatty acid oxidation and browning, and decreased expression of genes promoting fatty acid synthesis, triglyceride synthesis, and inflammation in adipose tissue. Conclusion: CHS‐131 improves liver histology in a DIO and biopsy‐confirmed mouse model of NASH by altering the hepatic lipidome, reducing insulin resistance, and improving lipid metabolism and inflammation in adipose tissue.

Empagliflozin Improves Metabolic and Hepatic Outcomes in a Non-Diabetic Obese Biopsy-Proven Mouse Model of Advanced NASH

“…Nevertheless, the reported effects of both studies argue for mild effects of empagliflozin in non-diabetic conditions, which thus necessitates a longer duration of treatment in order to achieve relevant hepatic benefits. In agreement with the above, when comparing the effects of empagliflozin with the effects of medications of other classes (i.e., liraglutide (glucagon-like peptide 1 receptor analogue), elafibranor (peroxisome proliferator-activated receptor alpha/delta agonist) or CHS-131 (selective peroxisome proliferator-activated receptor gamma modulator)) in the same mouse model experimental setting and for the same duration of treatment [19,20], the improvement in NAS score was more modest with empagliflozin, which suggested again weaker hepatic actions at normal/slightly elevated glucose levels compared with the other medications.…”

“…The study design and methodology have been previously described [19,20]. Briefly, male C57BL/6JRj mice were fed an AMLN diet (D09100301, Research Diets Inc., New Brunswick, NJ, USA) that consisted of 40% fat, 2% cholesterol and 22% fructose for 36 weeks before the study initiation.…”

“…Another group that consisted of mice of a similar age fed a normal chow diet was also included. The results regarding the other treatments have been previously published [19,20]. In the current analysis, we focused on DIO-NASH mice that received empagliflozin (n = 13, DIO-NASH + empagliflozin) at a dose of 10 mg/kg/day and we compared the findings with DIO-NASH mice treated with the vehicle (n = 13, DIO-NASH + vehicle) for 12 weeks.…”

PPARgamma in Metabolism, Immunity, and Cancer: Unified and Diverse Mechanisms of Action

“…As indicated earlier, new generations of ligands, referred to as noncanonical agonist ligands (NALs) and selective PPARy modulators (SPPARMs), hold promise in that respect. In fact, very recently, it has been shown how selective modulators of PPARy can improve liver histology without affecting body weight in biopsy-confirmed mouse model of nonalcoholic steatohepatitis (NASH) (148).…”

Making progress towards a better pathophysiological understanding and more promising therapeutic options for treating non-alcoholic steatohepatitis (NASH)/DASH (dysmetabolism associated steatohepatitis)

“…In brief, they showed that when Hrd1 (a subunit of the endoplasmic reticulum-associated degradation), is activated in hepatocytes, Acly (a major enzyme regulating lipogenesis) is degraded via ubiquitin modification, leading to hepatic steatosis amelioration and insulin sensitivity enhancement [37]. A great promise is also offered by selective PPAR-γ modulators, such as CHS-131 [62] that will need to be further assessed, as well as by medications that act early in the spectrum of the pathophysiology, such as glucagon-like peptide (GLP)-1 agonists, that can decrease liver fat, thus altering the natural history of the disease [26,[63][64][65]. It follows that relevant clinical trials are expected with great anticipation.…”