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Therapeutic potential of mitochondrial uncouplers for the treatment of metabolic associated fatty liver disease and NASH.

ABSTRACT:

Background

Mitochondrial uncouplers shuttle protons across the inner mitochondrial membrane via a pathway that is independent of adenosine triphosphate (ATP) synthase, thereby uncoupling nutrient oxidation from ATP production and dissipating the proton gradient as heat. While initial toxicity concerns hindered their therapeutic development in the early 1930s, there has been increased interest in exploring the therapeutic potential of mitochondrial uncouplers for the treatment of metabolic diseases.

Scope of review

In this review, we cover recent advances in the mechanisms by which mitochondrial uncouplers regulate biological processes and disease, with a particular focus on metabolic associated fatty liver disease (MAFLD), nonalcoholic hepatosteatosis (NASH), insulin resistance, and type 2 diabetes (T2D). We also discuss the challenges that remain to be addressed before synthetic and natural mitochondrial uncouplers can successfully enter the clinic.

Major conclusions

Rodent and non-human primate studies suggest that a myriad of small molecule mitochondrial uncouplers can safely reverse MAFLD/NASH with a wide therapeutic index. Despite this, further characterization of the tissue- and cell-specific effects of mitochondrial uncouplers is needed. We propose targeting the dosing of mitochondrial uncouplers to specific tissues such as the liver and/or developing molecules with self-limiting properties to induce a subtle and sustained increase in mitochondrial inefficiency, thereby avoiding systemic toxicity concerns.

SUBMITTER: Goedeke L

PROVIDER: S-EPMC8085597 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundMetabolic associated fatty liver disease (MAFLD) is a novel terminology introduced in 2020 to provide a more accurate description of fatty liver disease associated with metabolic dysfunction. It replaces the outdated term nonalcoholic fatty liver disease (NAFLD) and aims to improve diagnostic criteria and tailored treatment strategies for the disease. NAFLD, the most prevalent liver disease in western industrialized nations, has been steadily increasing in prevalence and is associated with serious complications such as cirrhosis and hepatocellular carcinoma. It is also linked to insulin resistance syndrome and cardiovascular diseases. However, current studies on NAFLD have limitations in meeting necessary histological endpoints.ObjectiveThis literature review aims to consolidate recent knowledge and discoveries concerning MAFLD, integrating the diverse aspects of the disease. Specifically, it focuses on analyzing the diagnostic criteria for MAFLD, differentiating it from NAFLD and alcoholic fatty liver disease (AFLD), and exploring the epidemiology, clinical manifestations, pathogenesis, and management approaches associated with MAFLD. The review also explores the associations between MAFLD and other conditions. It discusses the heightened mortality risk associated with MAFLD and its link to chronic kidney disease (CKD), showing that MAFLD exhibits enhanced diagnostic accuracy for identifying patients with CKD compared to NAFLD. The association between MAFLD and incident/prevalent CKD is supported by cohort studies and meta-analyses.ConclusionThis literature review highlights the importance of MAFLD as a distinct terminology for fatty liver disease associated with metabolic dysfunction. The review provides insights into the diagnostic criteria, associations with CKD, and management approaches for MAFLD. Further research is needed to develop more accurate diagnostic tools for advanced fibrosis in MAFLD and to explore the underlying mechanisms linking MAFLD with other conditions. This review serves as a valuable resource for researchers and healthcare professionals seeking a comprehensive understanding of MAFLD.