Activation of Liver AMPK with PF-06409577 Corrects NAFLD and Lowers Cholesterol in Rodent and Primate Preclinical Models

Abstract

Dysregulation of hepatic lipid and cholesterol metabolism is a significant contributor to cardiometabolic health, resulting in excessive liver lipid accumulation and ultimately non-alcoholic steatohepatitis (NASH). Therapeutic activators of the AMP-Activated Protein Kinase (AMPK) have been proposed as a treatment for metabolic diseases; we show that the AMPK β1-biased activator PF-06409577 is capable of lowering hepatic and systemic lipid and cholesterol levels in both rodent and monkey preclinical models. PF-06409577 is able to inhibit de novo lipid and cholesterol synthesis pathways, and causes a reduction in hepatic lipids and mRNA expression of markers of hepatic fibrosis. These effects require AMPK activity in the hepatocytes. Treatment of hyperlipidemic rats or cynomolgus monkeys with PF-06409577 for 6 weeks resulted in a reduction in circulating cholesterol. Together these data suggest that activation of AMPK β1 complexes with PF-06409577 is capable of impacting multiple facets of liver disease and represents a promising strategy for the treatment of NAFLD and NASH in humans.

Glucose availability but not changes in pancreatic hormones sensitizes hepatic AMPK activity during nutritional transition in rodents

“…AMPK has a high therapeutic potential for the management of dysregulated metabolism in the liver. Notably, pharmacological AMPK activation has shown beneficial effects in the treatment of liver steatosis (10,43,50,51). We have shown that drug-induced AMPK activation decreases hepatic lipid accumulation, both by inhibiting lipid synthesis and by stimulating fatty-acid oxidation (10).…”

AMP-activated protein kinase: the current landscape for drug development

“…Acetyl-CoA is also converted to malonyl-CoA, the first committed step in fatty acid synthesis, by ACC, which exists as two distinct isoforms: ACC1, which is predominately expressed in lipogenic tissues such as liver and adipose tissue, and ACC2, which is more common in heart and skeletal muscle. The inhibitory effects of AMPK on fatty acid synthesis require phosphorylation of ACC1 and ACC2, as mice lacking these phosphorylation sites have elevated ACC activity, malonyl-CoA and fatty acid synthesis and are also insensitive to AMPK activators 25,74,75 .…”

“…More recently, a number of small molecules have been identified that directly activate AMPK. Most of these compounds bind in a specific pocket formed by an interaction between the α and β subunits 22 , termed the allosteric drug and metabolite (ADaM) site 23 , and studies demonstrating preclinical and clinical efficacy of these activators are beginning to emerge [24][25][26][27] . For example, O304 has recently been shown to reduce fasting plasma glucose and blood pressure in individuals with type 2 diabetes taking metformin 28 .…”

Targeting the Inositol Pyrophosphate Biosynthetic Enzymes in Metabolic Diseases

“…Deregulation of AMPK is observed in obesity, diabetes and other metabolic diseases [29,[100][101][102][103][104][105][106][107][108][109][110][111][112][113][114][115]117]. Accordingly, direct or indirect pharmacologic AMPK activators reduce obesity, insulin resistance and NAFLD and NASH [110,112,[118][119][120][121][122][123][124]. Metformin, the most prescribed anti-diabetic drug that suppresses hepatic glucose production [125,126], exerts its effects partly via indirect activation of AMPK [110].…”

“…Moreover, the direct AMPK activator [122] CNX-012-570 enhances adipose tissue browning mediated energy expenditure, reduces body weight and NAFLD in mice [123]. PF-06409577 lowers lipid/cholesterol, and reduces hepatic lipid-biosynthetic/fibrotic genes in rodents and primates [124]. PXL770 (Poxel Pharma, Lyon, France) is in Phase-2a trials for NASH.…”