Mugagga Kalyesubula
Ramgopal Mopuri
Jimmy Asiku
Alexander Rosov
Sara Yosefi
Nir Edery
Samuel Bocobza
Uzi Moallem
Hay Dvir

Fatty 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., nonalcoholic fatty liver disease, generally develops due to overnutrition and sedentary lifestyle and has yet no approved drug therapy. We earlier developed a relevant large-animal model in which overnourished sheep raised on a highcalorie 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 the liver-fattening diet. The thiamine treatment also lowered the hyperglycemia and increased the liver's glycogen content, 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 fats. However, at the gene-expression level, more pronounced effects were observed on lipid-droplet formation and lipidation of VLDL, suggesting that thiamine may affect lipids metabolism not only through its known classical coenzyme roles. This discovery of the potent anti-steatotic effect of thiamine may prove clinically useful in managing fatty liver-related disorders.