Abstract
ABSTRACTFatty liver is an abnormal metabolic condition of excess intrahepatic fat. This condition, referred to as hepatic steatosis, is tightly associated with chronic liver disease and systemic metabolic morbidity. The most prevalent form in humans, i.e. non-alcoholic fatty liver, generally develops due to overnutrition and sedentary lifestyle, and has as yet no approved drug therapy. Previously, we have developed a relevant large-animal model in which overnourished sheep raised on a high-calorie carbohydrate-rich diet develop hyperglycemia, hyperinsulinemia, insulin resistance, and hepatic steatosis. Here, we tested the hypothesis that treatment with thiamine (vitamin B1) can counter the development of hepatic steatosis driven by overnutrition. Remarkably, the thiamine-treated animals presented with completely normal levels of intrahepatic fat, despite consuming the same amount of liver-fattening diet. Thiamine treatment also decreased hyperglycemia and increased the glycogen content of the liver, but it did not improve insulin sensitivity, suggesting that steatosis can be addressed independently of targeting insulin resistance. Thiamine increased the catalytic capacity for hepatic oxidation of carbohydrates and fatty acids. However, at gene-expression levels, more-pronounced effects were observed on lipid-droplet formation and lipidation of very-low-density lipoprotein, suggesting that thiamine affects lipid metabolism not only through its known classic coenzyme roles. This discovery of the potent anti-steatotic effect of thiamine may prove clinically useful in managing fatty liver-related disorders.This article has an associated First Person interview with the joint first authors of the paper.
Highlights
To identify molecular signals associated with the observed phenotypes, we employed differential expression analyses of selected genes involved in carbohydrate and lipid catabolism, synthesis, transport and storage, since improper balance between these metabolic pathways may lead to abnormal accumulation of intrahepatic fat (Kawano and Cohen, 2013)
It is unlikely that inflammation played a main role in the development of steatosis in this model or in its reversal by thiamine. Since both inflammation and oxidative stress have been extensively documented in obesity and metabolic dysfunction-associated FL disease (MAFLD) (Ibrahim et al, 2018; Tilg et al, 2020), we investigated their association with overnutrition and thiamine intervention, by comparing transcript levels of common proinflammatory cytokines and antioxidants
In this study, we demonstrated the potential of pharmacological thiamine therapy to address hepatic steatosis resulting from overnutrition
Summary
To better reflect the tight relationship of NAFLD with systemic metabolic dysfunction, such as insulin resistance and dyslipidemia, and its continuum of liver abnormalities, its coexistence with other liver diseases or concomitant to alcohol consumption, an alternative name, i.e. metabolic dysfunction-associated FL disease (MAFLD), has recently been proposed (Eslam et al, 2020a,b). We have adopted this moreinclusive term in the following
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