Diet-induced induction of hepatic serine/threonine kinase STK38 triggers proinflammation and hepatic lipid accumulation

Apr 7, 2023The Journal of biological chemistry

Diet-driven increase of liver enzyme STK38 linked to inflammation and fat buildup in the liver

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Abstract

HFD induces the expression of hepatic serine/threonine kinase 38 (STK38), which is associated with systemic inflammation and insulin resistance.

Chronic overnutrition, such as a high-fat diet, is linked to insulin resistance and inflammation.
Ectopic expression of STK38 in mouse liver results in a lean NAFLD phenotype, characterized by hepatic inflammation and insulin resistance.
Depleting hepatic STK38 in mice on a high-fat diet significantly reduces inflammation and improves insulin sensitivity.
STK38 promotes inflammation by binding to Tank-Binding protein Kinase 1 and facilitating the release of proinflammatory cytokines.
STK38 also contributes to fat accumulation in the liver by enhancing fat production through reduced signaling in the AMPK-ACC pathway.

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Nonalcoholic fatty liver disease (NAFLD) is one of the most common liver diseases worldwide. Although the involvement of chronic overnutrition, systemic inflammation, and insulin resistance in the development of NAFLD is well-established, however, the associations among these remain to be elucidated. Several studies have reported that chronic overnutrition, such as excessive consumption of fats (high-fat diet, HFD), can cause insulin resistance and inflammation. However, the mechanisms by which HFD exerts inflammation and thereby promotes insulin resistance and intrahepatic fat accumulation remain poorly understood. Here, we show that HFD induces the expression of hepatic serine/threonine kinase 38 (STK38), which further induces systemic inflammation leading to insulin resistance. Notably, ectopic expression of STK38 in mouse liver leads to lean NAFLD phenotype with hepatic inflammation, insulin resistance, intrahepatic lipid accumulation, and hypertriglyceridemia in mice fed on a regular chow diet. Further, depletion of hepatic STK38 in HFD-fed mice remarkably reduces proinflammation, improves hepatic insulin sensitivity, and decreases hepatic fat accumulation. Mechanistically, two critical stimuli are elicited by STK38 action. For one stimulus, STK38 binds to Tank-Binding protein Kinase 1 and induces Tank-Binding protein Kinase 1 phosphorylation to promote NF-κβ nuclear translocation that mobilizes the release of proinflammatory cytokines and eventually leads to insulin resistance. The second, stimulus involves intrahepatic lipid accumulation by enhanced de novo lipogenesis via reducing the AMPK-ACC signaling axis. These findings identify STK38 as a novel nutrient-sensitive proinflammatory and lipogenic factor in maintaining hepatic energy homeostasis, and it provides a promising target for hepatic and immune health.

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Diet-induced induction of hepatic serine/threonine kinase STK38 triggers proinflammation and hepatic lipid accumulation

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