Dual Effects of Lipid Metabolism on Osteoblast Function

Abstract

The skeleton is a dynamic and metabolically active organ with the capacity to influence whole body metabolism. This newly recognized function has propagated interest in the connection between bone health and metabolic dysfunction. Osteoblasts, the specialized mesenchymal cells responsible for the production of bone matrix and mineralization, rely on multiple fuel sources. The utilization of glucose by osteoblasts has long been a focus of research, however, lipids and their derivatives, are increasingly recognized as a vital energy source. Osteoblasts possess the necessary receptors and catabolic enzymes for internalization and utilization of circulating lipids. Disruption of these processes can impair osteoblast function, resulting in skeletal deficits while simultaneously altering whole body lipid homeostasis. This article provides an overview of the metabolism of postprandial and stored lipids and the osteoblast's ability to acquire and utilize these molecules. We focus on the requirement for fatty acid oxidation and the pathways regulating this function as well as the negative impact of dyslipidemia on the osteoblast and skeletal health. These findings provide key insights into the nuances of lipid metabolism in influencing skeletal homeostasis which are critical to appreciate the extent of the osteoblast's role in metabolic homeostasis.

Keywords: bone mass; dyslipidemia; fatty acid metabolism; lipoproteins; osteoblast.

Figure 1

Overview of tissue-targeted lipid metabolism. Ingested lipids are broken down in the intestinal lumen and internalized by enterocytes of the small intestine. The water insoluble triglycerides and cholesterol are repackaged into chylomicrons and travel through the lymphatic system and into the circulatory system where they engage lipoprotein lipase (LPL) on the surface of capillary endothelial cells. The hydrolyzed triglycerides result in release of free fatty acids that are taken up by adipose tissue and the skeleton. The remaining chylomicron remnants (CR) are cleared by the liver via the apolipoprotein E (ApoE) receptor. CR-derived cholesterol and free fatty acids and circulating glucose are used for de novo lipogenesis, generating ATP for the liver, or repackaged into very low-density lipoproteins (VLDL). VLDL particles are released into the circulation where they engage LPL and release free fatty acids, which are also available for uptake. The remaining low-density lipoprotein (LDL) are internalized by cells expressing the low-density lipoprotein receptor (LDLR) including adipocytes and osteoblasts. This figure was created using Servier Medical Art image templates under a Creative Commons Attribution 3.0 Unported License.

Figure 2

Lipid- flux between the adipocyte and osteoblast. White adipose tissue is the primary storage depot of lipids during excess consumption, which are subsequently released when energy expenditure exceeds caloric intake. Esterified fatty acids are stored in the adipocytes as triglycerides and are hydrolyzed by the rate limiting enzyme, adipose triglyceride lipase (ATGL), into diglycerides. Diglycerides are hydrolyzed into monoglycerides by hormone sensitive lipase (HSL) and further into fatty acids by monoacyglycerol lipase (MGL), which are then released into circulation. Adipocyte uptake of glucose is metabolized to acetyl-CoA and used for de novo fatty acid synthesis. These newly synthesized fatty acids are another lipid source for the osteoblast. LDL-derived fatty acids and uptake of circulating free fatty acids via CD36/FATPs are vital energy sources for the osteoblast. These internalized free fatty acids are converted into acyl-CoA by fatty acyl-CoA synthase. Very long chain fatty acids (VLCFAs) (more than 22 carbons) are first shortened by the peroxisome. Acyl-CoA is transported to the mitochondrial matrix by a carnitine exchange system in order to undergo β-oxidation. The product, acetyl-CoA is transferred to the TCA cycle and electron transport chain for generation of ATP. This figure was created using Servier Medical Art image templates under a Creative Commons Attribution 3.0 Unported License.

Figure 3

Skeletal deficits elicited by HFD-induced hyperlipidemia. A high fat diet (HFD) induces extensive systemic metabolic and skeletal changes including increases in circulating low density lipoprotein (LDL) and triglycerides (TG). This hyperlipidemic state impacts many nuances of osteoblast function and homeostasis including decreases in Wnt signaling and PTH responsiveness, insulin resistance, and increased RANKL. This results in decreased osteoblast activity and increased osteoclast activity ultimately contributing to poor skeletal health. This figure was created using Servier Medical Art image templates under a Creative Commons Attribution 3.0 Unported License.