The Thermoneutrality Effect: A Comprehensive Study of its Influence on Liver Pathology in Alcohol-Associated Liver Disease

Abstract

The thermoneutral zone (TNZ) of an endotherm encompasses the ambient temperature range at which it doesn't require metabolic compensation. Standard housing temperatures for laboratory mice (≈22°C) fall below their TNZ (≈30°C), fostering thermal stress. This notion has raised concerns on the translational validity of murine models housed at standard temperatures, since humans are typically housed at their TNZ, and thus exempt from the thermal stress. Hence, housing mice at their TNZ could improve their suitability as model organisms in biomedical research. Chronic alcoholism leads to Alcohol-associated liver disease (ALD), which is characterised by increased white adipose tissue lipolysis, fatty acid translocation to the liver, and hepatic de novo lipogenesis, culminating in steatosis. Hepatic alcohol metabolism drives hepatocyte damage, dysbiosis, inflammation, and oxidative stress, exacerbating liver pathology and driving the transition into more advanced clinical stages. Furthermore, as mitochondria constitute major sources of pro-oxidant species, an imbalance favouring these over antioxidants induces oxidative stress, a key driver of mitochondrial dysfunction. Consequently, this research project investigates whether thermoneutral housing could potentiate alcohol-driven liver pathology using an acute-on-chronic murine model of oral ethanol feeding. Oxidative stress, alcohol metabolism, mitochondrial morphology and function, inflammation, fibrosis, and mitochondrial cholesterol trafficking were assessed via biochemical assays, quantitative reverse transcription polymerase chain reaction (RT-qPCR), extracellular flux assay, microscopy, Western blot, and immunostaining techniques.