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.


Hepatic activation of protein kinase C (PKC) isoforms by diacylglycerol (DAG) promotes insulin resistance and contributes to the development of type 2 diabetes (T2D). The closely related protein kinase D (PKD) isoforms act as effectors for DAG and PKC. Here, we showed that PKD3 was the predominant PKD isoform expressed in hepatocytes and was activated by lipid overload. PKD3 suppressed the activity of downstream insulin effectors including the kinase AKT and mechanistic target of rapamycin complex 1 and 2 (mTORC1 and mTORC2). Hepatic deletion of PKD3 in mice improved insulin-induced glucose tolerance. However, increased insulin signaling in the absence of PKD3 promoted lipogenesis mediated by SREBP (sterol regulatory element-binding protein) and consequently increased triglyceride and cholesterol content in the livers of PKD3-deficient mice fed a high-fat diet. Conversely, hepatic-specific overexpression of a constitutively active PKD3 mutant suppressed insulin-induced signaling and caused insulin resistance. Our results indicate that PKD3 provides feedback on hepatic lipid production and suppresses insulin signaling. Therefore, manipulation of PKD3 activity could be used to decrease hepatic lipid content or improve hepatic insulin sensitivity.

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