RLA8—A New and Highly Effective Quadruple PPAR-α/γ/δ and GPR40 Agonist to Reverse Nonalcoholic Steatohepatitis and Fibrosis

Abstract

Nonalcoholic fatty liver disease (NAFLD) is a very common chronic hepatic disease, with nonalcoholic steatohepatitis (NASH) as a major and severe subcategory that can lead to cirrhosis and hepatocellular carcinoma, and thereby to a high mortality rate. Currently, there has been no approved drug to treat NAFLD or NASH. The current study has presented RLA8, a novel and balanced quadruple agonist for hepatic lipid metabolism and inflammation-related peroxisome proliferator-activated receptors (PPARs)-a/g/d and G protein-coupled receptor 40 (GPR40), as a NASH drug candidate. The efficacy of RLA8 to treat NASH was evaluated in vivo using two mouse models induced by methionine/choline-deficient diet or by high-fat diet, respectively. RLA8 was shown to improve serum alanine aminotransferase and high-density lipoprotein cholesterol levels, reduce hepatic free fatty acid and triglyceride levels, and alleviate insulin resistance. Cytokine and lipoperoxide analysis revealed that RLA8 could reduce oxidative stress and inflammation. Histochemical and morphologic examination of mouse livers showed that RLA8 could improve pathologic changes such as steatosis, ballooning, collagen fiber, and inflammation. Polymerase chain reaction and Western blot analyses proved that RLA8 could result in PPARs and GPR40 activation, accompanied by upregulation of the 59AMP-activated protein kinase-acetyl-CoA carboxylase pathway and inhibition of the expression of lipogenic genes and proteins, which provided more insights into its action mechanisms. In summary, RLA8 has significantly better efficacy to improve NASH-induced liver damage such as steatosis, inflammation, and fibrosis, and, consequently, it represents a new and highly promising NASH drug candidate that is worthy of further investigation and development.

S100A16, a novel lipogenesis promoting factor in livers of mice and hepatocytes in vitro

“…Is there any special interaction between AMPK and PPARγ? It is not clear yet, but in some studies, AMPK and PPARγ always increase and decrease simultaneously (H. Li et al, ; M. Li et al, ; S. H. Liu, Chiu, Huang, & Chiang, ; Zhang et al, ). The relationship between AMPK and PPARγ needs further study.…”

The GPR40 Full Agonist SCO-267 Improves Liver Parameters in a Mouse Model of Nonalcoholic Fatty Liver Disease without Affecting Glucose or Body Weight

“…Recently, RLA8, a quadruple agonist for peroxisome proliferator activated receptor-a/g/d and GPR40, was shown to have therapeutic efficacy in NASH mouse models (Li et al, 2019). This suggests that a strategy to activate multiple targets will likely prove to be effective in treating NASH.…”

Natural α-Glucosidase and Protein Tyrosine Phosphatase 1B Inhibitors: A Source of Scaffold Molecules for Synthesis of New Multitarget Antidiabetic Drugs

“…Finally, many efforts have been made to generate pan PPAR agonists combining the pharmacophore motif of PPAR-α, β, and ɣ agonists. Such molecules reduce lipids accumulation in the liver and improve liver damage, inflammation, fibrosis, and insulin resistance [ 18 , 19 ]. Although many new pan PPAR agonists have demonstrated their efficacy as antidiabetic drugs in the preclinical phase, subsequent clinical studies have shown their limitations and revealed their intrinsic toxicity.…”