Abstract:Hepatic steatosis is strongly associated with chronic liver disease and systemic metabolic disorder. Adipose lipolysis is a recognized principal source of intrahepatic fat in various metabolic disorders, including non-alcoholic fatty liver disease. We hypothesized that, in the premorbid state, hepatic de novo lipogenesis (DNL) driven by excess carbohydrates abundance might play a more significant role. We employed a novel nutritional model in sheep of two distinct carbohydrates abundances. During 4 months of t… Show more
“…1 ). These were, (i) a low-calorie (LC) diet known to maintain lean livers, (ii) a high-calorie (HC) diet known to stimulate FL ( Kalyesubula et al, 2020 ), and (iii) thiamine-treatment in combination with the HC diet (THC). Fig.…”
Section: Resultsmentioning
confidence: 99%
“…We have recently reported a large-animal nutritional model for FL, characterized by excessive carbohydrate intake, hyperglycemia and hyperinsulinemia, which collectively drove liver steatosis in sheep ( Kalyesubula et al, 2020 ). In a search for a pharmacological intervention with the potential to counteract both the systemic and liver-related metabolic aspects of this model, we decided to investigate thiamine, also known as vitamin B1, as a plausible beneficial agent, because of its fundamental role in energy metabolism.…”
Section: Introductionmentioning
confidence: 99%
“…The strong association between hepatic steatosis and hyperglycemia in the sheep model ( Kalyesubula et al, 2020 ), together with the accumulated evidence in respect to the relevant metabolic benefits of thiamine supplementation, motivated us to investigate the potential of high-dose thiamine treatment to counteract the overnutrition-driven steatosis that develops in this model.…”
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 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 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.
“…1 ). These were, (i) a low-calorie (LC) diet known to maintain lean livers, (ii) a high-calorie (HC) diet known to stimulate FL ( Kalyesubula et al, 2020 ), and (iii) thiamine-treatment in combination with the HC diet (THC). Fig.…”
Section: Resultsmentioning
confidence: 99%
“…We have recently reported a large-animal nutritional model for FL, characterized by excessive carbohydrate intake, hyperglycemia and hyperinsulinemia, which collectively drove liver steatosis in sheep ( Kalyesubula et al, 2020 ). In a search for a pharmacological intervention with the potential to counteract both the systemic and liver-related metabolic aspects of this model, we decided to investigate thiamine, also known as vitamin B1, as a plausible beneficial agent, because of its fundamental role in energy metabolism.…”
Section: Introductionmentioning
confidence: 99%
“…The strong association between hepatic steatosis and hyperglycemia in the sheep model ( Kalyesubula et al, 2020 ), together with the accumulated evidence in respect to the relevant metabolic benefits of thiamine supplementation, motivated us to investigate the potential of high-dose thiamine treatment to counteract the overnutrition-driven steatosis that develops in this model.…”
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 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 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.
“…All sheep were grown and maintained at the Volcani experimental farm in Rishon LeZion, Israel. The livers were harvested from ram lambs ( n = 30), which were raised on either ad libitum forage-based or concentrate-based rations to, respectively, induce lean or fatty livers for a previous study ( 25 ), and from pregnant ewes who died from severe PT ( n = 6). All livers were harvested immediately after death (pregnant ewes) or slaughter (lambs at ~7 months of age), and ~200 g of the left lobe of each liver was stored at −20°C until further biochemical analysis.…”
Section: Methodsmentioning
confidence: 99%
“…To test it, we have used the Folch method, with and without tissue sonication, in a comparative analysis of the intrahepatic-fat content. The ovine livers extracted post-mortem from grownup lambs ( 25 ) and from pregnant ewes presenting with clinical PT permitted precise quantification and sensitive analyses of the differences in extraction efficiencies between the two protocols across a wide range of liver-fat contents. The reported data for the pregnant ewes offer a reliable reference of intrahepatic fat content values in PT.…”
Fatty liver represents a significant metabolic pathology of excess intrahepatic fat in domestic animals and humans. Quantification of hepatic-fat content is therefore essential for diagnosis and investigation of liver and metabolic disease. However, the reproducibility of hepatic steatosis analysis is often low due to subjective and technical factors. We hypothesized that improvement in tissue-lipids extraction efficiency would contribute to the accuracy and precision of liver-fat determination. To test it, we investigated the effect of standardized tissue sonication on liver-fat quantification by the Folch method in sheep. Liver samples from grownup lambs of lean (n = 16) and fatty (n = 15) livers, and from pregnant ewes (n = 6) who died from pregnancy toxemia (PT), were used for hepatic-fat content determination with or without tissue sonication. In the grown lambs, an average hepatic-fat content of 6.6% was determined in sonicated compared to 5.1% in non-sonicated specimens (P = 0.0002). Similarly, in ewes with PT, an average of 12.5% was determined with sonication compared to 10.8% without it (P = 0.0006), and the reproducibility was higher with sonication (CV of 3.1 vs. 6.1%, respectively). Thus, tissue sonication improved the efficiency of liver-lipids extraction and was significant to the accuracy and precision of hepatic-fat determination. Enzymatic quantification of triglycerides was moderately correlated with the results obtained gravimetrically (r = 0.632, P < 0.005). The reported data provide reliable reference values for pregnancy toxemic sheep. The significant improvement in liver-fat quantification observed with the reported revised protocol is likely applicable to most mammals and humans.
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