Constitutive PI3K-AKT activation promotes steatohepatitis through de novo lipogenesis despite enhanced mitochondrial β-oxidation, essential fatty acid depletion and reduced lipid peroxidation
Background. Activation of de novo lipogenesis (DNL) is a major hallmark of steatotic liver disease (SLD), a highly prevalent group of diseases ranging from a harmless steatosis to more severe steatohepatitis, cirrhosis, and hepatocellular carcinoma. We interrogated herein the early alterations in liver proteome, transcriptome, lipidome, inflammation, fibrosis, and oxidative status in a mouse…
A mouse model study reveals that constitutive activation of the PI3K-AKT signaling pathway in hepatocytes leads to steatohepatitis, a severe liver condition. This activation results in hyperactive de novo lipogenesis (DNL), causing excessive fat accumulation within liver cells. Surprisingly, despite this DNL, the liver shows reduced lipid peroxidation, higher levels of glutathione (GSH), and improved metabolism.
The study also found that essential fatty acids, particularly linoleic and linolenic acids, are depleted in the liver. While dietary supplementation of linoleic acid slightly eased inflammation, it did not impact lipid peroxidation or reduce steatosis and fibrosis. However, pharmacological inhibition of DNL reduced steatosis, inflammation, and fibrosis, even with further decline in hepatic linoleic acid levels.
The results highlight that essential fatty acid depletion exacerbates liver inflammation and suggest that DNL plays a key role in steatohepatitis induced by constitutive PI3K-AKT activation.
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