Abstract
Lipids are the most energy‐dense components of the diet, and their overconsumption promotes obesity and diabetes. Dietary fat content has been linked to the lipid processing activity by the intestine and its overall capacity to absorb triglycerides (TG). However, the signaling cascades driving intestinal lipid absorption in response to elevated dietary fat are largely unknown. Here, we describe an unexpected role of the protein kinase D2 (PKD2) in lipid homeostasis. We demonstrate that PKD2 activity promotes chylomicron‐mediated TG transfer in enterocytes. PKD2 increases chylomicron size to enhance the TG secretion on the basolateral side of the mouse and human enterocytes, which is associated with decreased abundance of APOA4. PKD2 activation in intestine also correlates positively with circulating TG in obese human patients. Importantly, deletion, inactivation, or inhibition of PKD2 ameliorates high‐fat diet‐induced obesity and diabetes and improves gut microbiota profile in mice. Taken together, our findings suggest that PKD2 represents a key signaling node promoting dietary fat absorption and may serve as an attractive target for the treatment of obesity.
Highlights
The type of diet plays a major role in modulating organismal metabolism
As previous studies indicated that deletion of PKD1 kinase, in adipose tissue, promotes the expression of beige adipocyte-specific markers (Loffler et al, 2018), we have tested the expression of Ucp1, Cidea, Bmp7, Prdm16, Ppara, Pgc1a, Adrb3, Cidec, Myh2, Ckm, Mck, Slc6a8, Slc27a2, Ucp3, and Myh1 subcutaneous adipose tissue of Pkd2ki/ki and control Pkd2wt/wt mice fed high-fat diet (HFD) and except Slc6a8, which was downregulated in the mice without active protein kinase D2 (PKD2); there were no significant changes in the expression of these genes (Fig EV1A)
Our experiments suggest that PKD2 promotes lipid uptake in the intestine by acting directly in enterocytes
Summary
Diets containing elevated fat content are generally more energy dense, which promotes a positive energy balance and, obesity. The digestive system is the first site to be challenged by elevated levels of fat in the diet. After emulsification of ingested fat by bile acids, triglycerides are broken down into glycerol, monoglyceride, and fatty acids (FAs) by pancreatic lipases in the small intestine lumen (Lowe, 2002; Hussain, 2014). FAs and monoglycerides or glycerol are reesterified at the endoplasmic reticulum (ER). These monoglyceride and glycerol 3-phosphate pathways are responsible for the majority of TG synthesis in enterocytes (Yang & Nickels, 2015). TG are packed into pre-chylomicrons together with lipoproteins such as apolipoprotein B48 (APOB48) and apolipoprotein A4 (APOA4) by the microsomal transfer protein (MTTP)
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