High‐fat and high‐sucrose (western) diet induces steatohepatitis that is dependent on fructokinase
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...fat diet, much more severe fatty liver occurs in mice.(132) One potential explanation is that, like fructose, high-fat diets induce mitochondrial oxidative stress....
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...Nevertheless, mice lacking fructokinase show marked protection from fatty liver and insulin resistance, highlighting the key role of fructose in western diet-induced NAFLD.(132) Alcohol ingestion is well known to induce fatty liver and chronic liver disease that can be histologically similar to NAFLD....
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...KHK expression is increased in patients with NAFLD, and inhibition of KHK leads to decreased fatty liver and decreased liver inflammation in mice fed high-fat high-sucrose diet [98]....
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...Because liver expresses the highest level of Khk-C and high fructose intake causes liver-related pathologies (Ishimoto et al., 2012, 2013; Lanaspa et al., 2013; Zhang et al., 2017), it has been assumed that liver is the primary site of dietary fructose metabolism, with few studies examining the…...
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...Small Intestine Is a Primary Organ for Dietary Fructose Clearance Transcriptional data show the highest expression of Khk-C in the liver, suggesting that liver is the key site of fructose catabolism (Ishimoto et al., 2012, 2013; Lanaspa et al., 2013)....
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...This assumption is consistent with the liver’s general metabolic importance, high levels of expression of fructose catabolic enzymes, and sensitivity to fructose, which causes fatty liver disease (Ishimoto et al., 2012, 2013; Lanaspa et al., 2013; Zhang et al., 2017)....
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"High‐fat and high‐sucrose (western)..." refers background in this paper
...In older adults, daily fructose consumption was associated with increased hepatic inflammation and hepatocyte ballooning.8 The administration of fructose alone or sugary beverages containing fructose increased de novo lipogenesis and hepatic triglyceride storage in humans.15-17 These observations suggest that fructose intake may have an important role in the pathogenesis of NAFLD.7,18-20 High fructose consumption causes hepatic steatosis accompanied with intracellular phosphate depletion.21 Fructose is primarily metabolized by fructokinase (ketohexokinase), which exists in two isoforms: fructokinase C and fructokinase A. Fructokinase C is the principal isoform in the liver and is a rapid phosphorylator, and metabolizes fructose to fructose-1phosphate rapidly, resulting in transient depletion of intracellular phosphate and adenosine triphosphate (ATP)....
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...Subjects with NAFLD also have a history of higher intake of fructose-containing soft drinks, with evidence for increased expression of fructose-metabolizing enzymes in their liver.(7) After controlling for age, sex, body mass index (BMI), and total calorie intake, daily fructose consumption was associated with lower steatosis grade and higher fibrosis stage....
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...Indeed, the administration of either intravenous or oral fructose to humans can result in transient ATP depletion and is greater in subjects with NAFLD.28-31 The greater ATP depletion in NAFLD may result from higher levels of fructokinase,7 as higher levels of fructokinase result in greater metabolic effects for the same dose of fructose.23 Subjects with NAFLD who have a higher fructose intake show a greater ATP depletion to intravenous fructose.28 In turn, the nucleotide turnover associated with fructose metabolism results in the production of uric acid, which can induce mitochondrial oxidative stress and the accumulation of lipids in the liver.22-24 Consistent with these findings, we observed an increase in hepatic uric acid levels with increased superoxide generation, increased mitochondrial NOX4, and a decrease in the mitochondrial antioxidant MnSOD in the WT HFHSD fed mice but not in KHK A/C KO mice fed the same diet....
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...Classic Western diets are high in both saturated fat and sugar, and both have been implicated in the development of NAFLD....
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...These observations suggest that fructose intake may have an important role in the pathogenesis of NAFLD.(7,18-20) High fructose consumption causes hepatic steatosis accompanied with intracellular phosphate depletion....
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"High‐fat and high‐sucrose (western)..." refers background in this paper
...N onalcoholic fatty liver disease (NAFLD) is the most common liver disease in children and adults, and is a hepatic manifestation of obesity and the metabolic syndrome.(1) NAFLD includes two entities that have a different prognosis: simple hepatic steatosis with no adverse sequelae, and nonalcoholic steatohepatitis (NASH), which has a proven potential to progress to cirrhosis and even hepatocellular carcinoma....
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