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

Area of Science:

• Metabolic disease
• Hepatology
• Molecular signaling

Background:

• Protein kinase C (PKC) activation by diacylglycerol (DAG) in the liver contributes to insulin resistance and type 2 diabetes (T2D).
• Protein kinase D (PKD) isoforms are downstream effectors of DAG and PKC signaling pathways.

Purpose of the Study:

• To investigate the role of the predominant hepatic PKD isoform, PKD3, in regulating insulin signaling and lipid metabolism.
• To determine the therapeutic potential of targeting PKD3 for metabolic diseases like T2D.

Main Methods:

• Examined PKD3 expression and activation in response to lipid overload in hepatocytes.
• Utilized a hepatic deletion model of PKD3 in mice fed a high-fat diet.
• Overexpressed a constitutively active PKD3 mutant in the liver.

Main Results:

• PKD3 is the predominant PKD isoform in hepatocytes and is activated by lipid overload.
• PKD3 suppresses hepatic insulin signaling pathways, including AKT and mTORC1/2.
• Hepatic deletion of PKD3 improved glucose tolerance but increased hepatic lipogenesis and lipid content.
• Overexpression of active PKD3 induced insulin resistance and suppressed insulin signaling.

Conclusions:

• PKD3 acts as a negative feedback regulator of hepatic lipid production and insulin signaling.
• Targeting PKD3 activity may offer a dual approach to reduce hepatic lipid accumulation and enhance insulin sensitivity.