In tissue samples from the small intestine of deceased humans, those with obesity and NASH show lower levels of proteins that maintain intestinal barrier integrity and higher levels of proteins...
Mechanism
Synthesis from 1 study
When someone with obesity eats a lot of fructose, a harmful enzyme in their gut gets overactive and starts breaking down the glue that holds gut cells together. This lets bacteria and toxins leak into the blood, which then damage the liver, making fat build up and scar tissue form. The same process...
Most probable mechanism
In people with obesity and liver disease, eating too much fructose causes a liver enzyme called CYP2E1 to become overactive in the gut. This enzyme produces harmful chemicals that damage the proteins holding gut cells together, causing them to break down and be removed by the cell’s waste system. As these proteins disappear, gaps form between gut cells, letting bacteria and toxins leak into the bloodstream. These toxins then travel to the liver, worsening fat buildup and scarring. At the same time, the same harmful chemicals also cause gut cells to die off faster, making the leak even worse.
Increased dietary fructose intake elevates expression and activity of CYP2E1 in intestinal epithelial cells.
Elevated CYP2E1 drives production of reactive oxygen and nitrogen species, including nitric oxide via induction of iNOS.
Reactive nitrogen species cause tyrosine nitration of tight junction proteins (ZO-1, occludin, claudin-1, claudin-4) and adherent junction proteins (β-catenin, E-cadherin).
Nitrated junctional proteins are tagged with ubiquitin and degraded by the proteasome, reducing their abundance in the intestinal epithelium.
Loss of junctional proteins disrupts the physical seal between intestinal cells, increasing paracellular permeability.
CYP2E1-driven oxidative stress activates JNK signaling, increasing expression of pro-apoptotic proteins (Bax, cleaved caspase-3) and triggering enterocyte apoptosis.
Enterocyte death and junctional degradation together compromise epithelial barrier integrity, allowing bacterial endotoxins to translocate into systemic circulation.
Circulating endotoxins activate hepatic stellate cells via TLR4 signaling, promoting their transformation into collagen-producing myofibroblasts.
Activated stellate cells deposit extracellular matrix proteins, driving liver fibrosis and amplifying hepatic inflammation.
Systemic nitrative stress and mitochondrial dysfunction reduce Sirt1 levels, impairing fatty acid oxidation and promoting lipid accumulation in hepatocytes.
Evidence from Studies
Supporting (1)
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Fructose Promotes Leaky Gut, Endotoxemia and Liver Fibrosis through CYP2E1-Mediated Oxidative and Nitrative Stress
Contradicting (0)
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