Validation of PAS Kinase, a Regulator of Hepatic Fatty Acid and Triglyceride Synthesis, as a Therapeutic Target for Nonalcoholic Steatohepatitis

Abstract

Hyperactivation of sterol regulatory element binding protein 1c (SREBP-1c), which transcriptionally induces expression of enzymes responsible for de novo lipogenesis and triglyceride (TG) formation, is implicated in nonalcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH) pathogenesis. Posttranslational SREBP-1c maturation and activation is stimulated by the protein per-arnt-sim kinase (PASK). PASK-knockout mice are phenotypically normal on a conventional diet but exhibit decreased hypertriglyceridemia, insulin resistance, and hepatic steatosis on a highfat diet. We investigated the effects of pharmacologic PASK inhibition using BioE-1115, a selective and potent oral PASK inhibitor, in Zucker fatty (fa)/fa) rats, a genetic model of obesity, dyslipidemia, and insulin resistance, and in a dietary murine model of NAFLD/NASH. Female Zucker (fa/fa) rats and lean littermate (fa/+) controls received BioE-1115 (3-100 mg/kg/day) and/or omega-3 fatty acids, and blood glucose, hemoglobin A1c, glucose tolerance, insulin, and serum TG were measured. C57BL/6J mice fed a high-fat/high-fructose diet (HF-HFrD) were treated with BioE-1115 (100 mg/kg/day) or vehicle. Body weight and fasting glucose were measured regularly; serum TG, body and organ weights, and liver TG and histology were assessed at sacrifice. Messenger RNA (mRNA) abundance of SREBP-1c target genes was measured in both models. In Zucker rats, BioE-1115 treatment produced significant dosedependent reductions in blood glucose, insulin, and TG (all greater than omega-3 fatty acids) and dose dependently restored insulin sensitivity assessed by glucose tolerance testing. In HF-HFrD mice, BioE-1115 reduced body weight, liver weight, fasting blood glucose, serum TGs, hepatic TG, hepatic fibrosis, hepatocyte vacuolization, and bile duct hyperplasia. BioE-1115 reduced SREBP-1c target mRNA transcripts in both models. Conclusion: PASK inhibition mitigates many adverse metabolic consequences associated with an HF-HFrD and reduces hepatic fat content and fibrosis. This suggests that inhibition of PASK is an attractive therapeutic strategy for NAFLD/NASH treatment. (Hepatology Communications 2020;4:696-707).

Role of Nutrient and Energy Sensors in the Development of Type 2 Diabetes

“…Thus PASK −/− mice under an HFD have lower blood glucose levels, improve their sensitivity to the action of insulin, preventing the appearance of insulin resistance, which in turn is correlated with smaller increases in body weight and improved lipid profile [112]. PASK pharmacologic inhibition likewise confirms its key role for restoring insulin sensitivity, and for reducing hepatic fat content and the fibrosis caused by an HFD [98].…”

“…PASK deficiency decreases insulin production, insulin resistance, body weight and hepatic triglyceride accumulation, while leading to increased glycogen storage, as well as metabolic rate [97]. Some of the effects observed in PASK −/− have also been confirmed using PASK pharmacologic inhibitors [98].…”

Storage and Utilization of Glycogen by Mouse Liver during Adaptation to Nutritional Changes Are GLP-1 and PASK Dependent

“…This involves highly regulated molecular mechanisms that control the expression and function of the transcription factors, enzymes and miRNAs in glucose and insulin signaling [ 20 , 24 ]. Pharmacologic inhibition of PASK also confirmed its capacity for improving insulin sensitivity, reducing nonalcoholic steatohepatitis caused by an HFD [ 35 ]. Accordingly, PASK has also been proposed as a possible target in the treatment of diabetes and obesity.…”

PAS Kinase: A Nutrient and Energy Sensor “Master Key” in the Response to Fasting/Feeding Conditions

“…All the differences due to PASK deficiency lead to an improvement in glucose tolerance and insulin sensitivity, preventing weight gain and alterations in triglyceride and blood cholesterol values (49). The effects of pharmacologic PASK inhibition also confirm its role restoring insulin sensitivity and reducing the hepatic fat content and fibrosis associated with HFDs (54).…”