A small molecule targeting ALOX12-ACC1 ameliorates nonalcoholic steatohepatitis in mice and macaques

Abstract

IMA-1 targets the ALOX12-ACC1 interaction to both prevent and treat NASH without inducing hyperlipidemia.

Multiple omics study identifies an interspecies conserved driver for nonalcoholic steatohepatitis

“…Whereas this study focuses on mechanistic and proof-of-concept evidence supporting the close correlation of ALOX12 with NASH progression and the potential of ALOX12 as a therapeutic target for NASH, our companion study focuses on the pharmacological treatment of NASH with new small-molecule chemicals ( 22 ). Limitations in this study include lacking a comprehensive analysis on the causal effects of ALOX12–12-HETE on NASH in large clinical cases.…”

“…This evidence directly explains the negative intracellular ALOX12-ACC2 interaction and the negligible effect of ALOX12 on ACC2 expression. In our companion paper (22), a protein structure-based docking algorithm suggested that amino acids 246 to 271 and 511 to 531 of ALOX12 contribute to its interaction with ACC1 N-terminal domain based on docking analysis. Here, we performed a co-IP assay and found that truncated ALOX12(246-271 and 511-531) failed to interact with the ACC1 N-terminal domain (fig.…”

The multifaceted role of ferroptosis in liver disease

“…Moreover, 12/15-lipoxygenase has been functionally connected to hydroperoxy-phosphatidylethanolamine-related ferroptosis [ 88 ]. Recently, arachidonate 12-lipoxygenase (ALOX-12) promotes the progression NASH via its interaction with acetyl-CoA carboxylase 1 (ACC1) [ 89 , 90 ]. However, whether ferroptosis plays a role in ALOX-12‒mediated NASH remains an open question.…”

Impact of NAFLD and its pharmacotherapy on lipid profile and CVD

“…Subsequently, malonyl-CoA is catalyzed by FASN and stearoyl-CoA desaturase 1 to form TGs, which are stored in hepatocytes [35]. At the same time, reduced malonyl-CoA levels repress the formation of polyunsaturated fatty acids (PUFAs), which subsequently enhance lipogenic gene expression and VLDL secretion [36][37][38] (Fig. 2).…”

“…The detrimental effect on lipid profile has been a major obstacle to the successful initiation of clinical application of ACC inhibitors. Possible approaches to address this obstacle include suppressing compensatory increases in lipogenic genes [76], enhancing hepatic lipid oxidation or lipid degradation in plasma [22], or fine-tuning ACC activity using moderate ACC inhibitors [37]. A phase 2a clinical study administered combined treatment with ACC inhibitors and diacylglycerol acyltransferase 2 (DGAT2) inhibitors to NAFLD patients [76].…”