Inhibition of Diacylglycerol Acyltransferase 2 Versus Diacylglycerol Acyltransferase 1: Potential Therapeutic Implications of Pharmacology

by Selleckchem | Nov 26 2023

Purpose: Hepatic steatosis due to altered lipid metabolism and accumulation of hepatic triglycerides is a hallmark of nonalcoholic fatty liver disease (NAFLD). Diacylglycerol acyltransferase (DGAT) enzymes, DGAT1 and DGAT2, catalyze the terminal reaction in triglyceride synthesis, making them attractive targets for pharmacologic intervention. There is a common misconception that these enzymes are related; however, despite their similar names, DGAT1 and DGAT2 differ significantly on multiple levels. As we look ahead to future clinical studies of DGAT2 inhibitors in patients with NAFLD and nonalcoholic steatohepatitis (NASH), we review key differences and include evidence to highlight and support DGAT2 inhibitor (DGAT2i) pharmacology.

Methods: Three Phase I, randomized, double-blind, placebo-controlled trials assessed the safety, tolerability, and pharmacokinetic properties of the DGAT2i ervogastat (PF-06865571) in healthy adult participants (Single Dose Study to Assess the Safety, Tolerability and Pharmacokinetics of PF-06865571 [study C2541001] and Study to Assess the Safety, Tolerability, and Pharmacokinetics of Multiple Doses of PF-06865571 in Healthy, Including Overweight and Obese, Adult Subjects [study C2541002]) or participants with NAFLD (2-Week Study in People With Nonalcoholic Fatty Liver Disease [study C2541005]). Data from 2 Phase I, randomized, double-blind, placebo-controlled trials of the DGAT1i PF-04620110 in healthy participants (A Single Dose Study of PF-04620110 in Overweight and Obese, Otherwise Healthy Volunteers [study B0961001] and A Multiple Dose Study of PF-04620110 in Overweight and Obese, Otherwise Healthy Volunteers [study B0961002]) were included for comparison. Safety outcomes were the primary end point in all studies, except in study C2541005, in which safety was the secondary end point, with relative change from baseline in whole liver fat at day 15 assessed as the primary end point. Safety data were analyzed across studies by total daily dose of ervogastat (5, 15, 50, 100, 150, 500, 600, 1000, and 1500 mg) or PF-04620110 (0.3, 1, 3, 5, 7, 10, 14, and 21 mg), with placebo data pooled separately across ervogastat and PF-04620110 studies.

Findings: Published data indicate that DGAT1 and DGAT2 differ in multiple dimensions, including gene family, subcellular localization, substrate preference, and specificity, with unrelated pharmacologic inhibition properties and differing safety profiles. Although initial nonclinical studies suggested a potentially attractive therapeutic profile with DGAT1 inhibition, genetic and pharmacologic data suggest otherwise, with common gastrointestinal adverse events, including nausea, vomiting, and diarrhea, limiting further clinical development. Conversely, DGAT2 inhibition, although initially not pursued as aggressively as a potential target for pharmacologic intervention, has consistent efficacy in nonclinical studies, with reduced triglyceride synthesis accompanied by reduced expression of genes essential for de novo lipogenesis. In addition, early clinical data indicate antisteatotic effects with DGAT2i ervogastat, in participants with NAFLD, accompanied by a well-tolerated safety profile.

Implications: Although pharmacologic DGAT1is are limited by an adverse safety profile, data support use of DGAT2i as an effective and well-tolerated therapeutic strategy for patients with NAFLD, NASH, and NASH with liver fibrosis.

Comments:

The provided passage discusses the research findings related to diacylglycerol acyltransferase enzymes (DGAT1 and DGAT2) and their potential as targets for pharmacological intervention in nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH). Here's a summary of the key points:

### Background:

Hepatic steatosis in NAFLD is characterized by altered lipid metabolism and accumulation of hepatic triglycerides. DGAT1 and DGAT2 enzymes play a crucial role in triglyceride synthesis and are potential targets for drug development.

### Key Differences Between DGAT1 and DGAT2:

1. **Gene Family:** DGAT1 and DGAT2 belong to different gene families.
2. **Subcellular Localization:** They are localized differently within cells.
3. **Substrate Preference and Specificity:** They have distinct preferences for substrates, indicating their different roles in lipid metabolism.
4. **Pharmacologic Inhibition Properties:** DGAT1 and DGAT2 respond differently to pharmacological inhibition.
5. **Safety Profiles:** They exhibit varying safety profiles, with DGAT1 inhibitors causing gastrointestinal adverse events.

### Research Methodology:

Several Phase I clinical trials were conducted to assess the safety, tolerability, and pharmacokinetic properties of DGAT2 inhibitor (DGAT2i) ervogastat (PF-06865571) in healthy participants and those with NAFLD. Comparative data from DGAT1 inhibitor (DGAT1i) PF-04620110 trials were also included.

### Findings:

1. **DGAT1 Inhibition:** Initial studies suggested DGAT1 inhibition as a potential therapeutic approach. However, adverse effects like nausea, vomiting, and diarrhea limited further clinical development.

2. **DGAT2 Inhibition:** DGAT2 inhibition showed consistent efficacy in nonclinical studies, reducing triglyceride synthesis and expression of lipogenesis-related genes. Early clinical data with DGAT2i ervogastat indicated antisteatotic effects in NAFLD participants, coupled with a well-tolerated safety profile.

### Implications:

Pharmacological DGAT1 inhibitors face limitations due to adverse effects, while DGAT2 inhibitors like ervogastat present a promising and well-tolerated therapeutic strategy for patients with NAFLD, NASH, and NASH with liver fibrosis.

In summary, the research suggests that DGAT2 inhibition could be a viable avenue for developing drugs to treat NAFLD and related liver conditions, offering a potential solution where DGAT1 inhibition fell short.