Research ArticleMetabolism

The kinase PKD3 provides negative feedback on cholesterol and triglyceride synthesis by suppressing insulin signaling

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Science Signaling  06 Aug 2019:
Vol. 12, Issue 593, eaav9150
DOI: 10.1126/scisignal.aav9150

A limit for liver lipid overload

Hepatocytes respond to insulin by accumulating triglycerides and cholesterol. Excessive lipid accumulation in the liver can result in nonalcoholic fatty liver disease (NAFLD), the more severe forms of which are risk factors for the development of liver cirrhosis and cancer. Mayer et al. found that activation of PKD3 by insulin signaling served as a negative feedback mechanism to prevent hepatic lipid accumulation. Mice lacking PKD3 in the liver showed increased insulin signaling, triglyceride and cholesterol synthesis, and steatosis in response to a high-fat diet. In contrast, overexpression of a constitutively active form of PKD3 attenuated insulin signaling in the liver and resulted in insulin resistance. Thus, PKD3 activity curtails insulin signaling and, therefore, lipid synthesis and accumulation in the liver.

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