ArticleMolecular metabolism2023
High-throughput screening identifies small molecule inhibitors of thioesterase superfamily member 1: Implications for the management of non-alcoholic fatty liver disease.
Article in Molecular metabolism, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 4 papers.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Who cites it
4 citing papers in PubMed, 3 citations in OpenAlex.
- Structure, Mutation, Functional Domain Roles and Medical Implications of Glycerol Kinase.The protein journal · 2026Review
- Acyl-CoA thioesterases and their derived lipid mediators: linking Acyl-CoA metabolic reprogramming to the tumor microenvironment.Frontiers in immunology · 2026Review
- ChREBP-mediated up-regulation of Them1 coordinates thermogenesis with glycolysis and lipogenesis in response to chronic stress.Science signaling · 2024Article
- Structure, function, and lipid sensing activity in the thioesterase superfamily.Biochemical Society transactions · 2024Review
Corrections and comments
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Authors and funding
14 authors at 6 institutions in 1 country.
Funding
Abstract
objectiveThioesterase superfamily member 1 (Them1) is a long chain acyl-CoA thioesterase comprising two N-terminal HotDog fold enzymatic domains linked to a C-terminal lipid-sensing steroidogenic acute regulatory transfer-related (START) domain, which allosterically modulates enzymatic activity. Them1 is highly expressed in thermogenic adipose tissue, where it functions to suppress energy expenditure by limiting rates of fatty acid oxidation, and is induced markedly in liver in response to high fat feeding, where it suppresses fatty acid oxidation and promotes glucose production. Them1
methodsA high-throughput small molecule screen was performed to identify promising inhibitors targeting the fatty acyl-CoA thioesterase activity of purified recombinant Them1.Counter screening was used to determine specificity for Them1 relative to other acyl-CoA thioesterase isoforms. Inhibitor binding and enzyme inhibition were quantified by biophysical and biochemical approaches, respectively. Following structure-based optimization, lead compounds were tested in cell culture.
resultsTwo lead allosteric inhibitors were identified that selectively inhibited Them1 by binding the START domain. In mouse brown adipocytes, these inhibitors promoted fatty acid oxidation, as evidenced by increased oxygen consumption rates. In mouse hepatocytes, they promoted fatty acid oxidation, but also reduced glucose production.
conclusionThem1 inhibitors could prove attractive for the pharmacologic management of NAFLD.
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Registered trials
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