Lipids in the Bone Marrow: An Evolving Perspective

Abstract

Because of heavy energy demands to maintain bone homeostasis, the skeletal system is closely tied to whole-body metabolism via neuronal and hormonal mediators. Glucose, amino acids, and fatty acids are the chief fuel sources for bone resident cells during its remodeling. Lipids, which can be mobilized from intracellular depots in the bone marrow, can be a potent source of fatty acids. Thus, while it has been suggested that adipocytes in the bone marrow act as "filler" and are detrimental to skeletal homeostasis, we propose that marrow lipids are, in fact, essential for proper bone functioning. As such, we examine the prevailing evidence regarding the storage, use, and export of lipids within the skeletal niche, including from both in vitro and in vivo model systems. We also highlight the numerous challenges that remain to fully appreciate the relationship of lipid turnover to skeletal homeostasis.

Keywords: adipocytes; bone; cholesterol; diet; energy; fat; osteoblasts.

Figure 1.

Schematic diagram of lipids and fatty acids found within the skeletal niche. These include chylomicron remnants, low density lipoproteins (LDL), high density lipoproteins (HDL), free fatty acids (FFA), and short chain fatty acids (SCFA). Glucose is depicted as it can serve as a substrate for fatty acid synthesis via de novo lipogenesis. All or some of these elements are presumed to be available to cells with the bone microenvironment including bone marrow adipocytes (yellow), osteoblasts and bone lining cells (blue), osteoclasts (pink), and osteocytes via vascularization. Bone marrow adipocytes are also capable of providing free fatty acid and glycerol.

Figure 2.

Cells within the skeletal niche utilize long chain free fatty acids (LCFA) for energy generation via two complimentary cellular catabolic processes of the carnitine shuttle and β-oxidation. (A) Long chain fatty acids (LCFA) destined for adenosine triphosphate (ATP) generation must first be activated and esterified to coenzyme A (CoA) via acyl-CoA synthetase long chain family members (ACSLs), which requires ATP and coenzyme A (CoA) yielding adenosine monophosphate (ANP) and inorganic pyrophosphate (PPi). Following these reactions the ‘carnitine shuttle’ transports fatty acyl groups via carnitine palmitoyltransferase I (CPTI) and II (CPTII), along with carnitine-acylcarnitine translocase (CACT) in to the mitochondria. (B) β-oxidation then utilizes two carbons of acyl-CoA by a series of reactions involving oxidation, hydration and cleavage ultimately generating acetyl-CoA from fatty acyl CoA. In additional to acetyl-CoA that can enter the Krebs cycle, β-oxidation also generates reducing equivalents FADH₂ and NADH. Every round of β-oxidation utilizes two carbons (−2C) to generate acetyl-CoA. Additionally cells within the skeletal niche can acquire cholesterol via low density lipoprotein (LDL)-LDL receptor (LDLR) endocytosis or the cholesterol biosynthetic pathway. (C) Circulating LDL particles will interact with LDL receptor (LDLR) on the cell surface which results in LDL-LDLR endocytosis. Within the cell these endosomes will fuse with the lysosome whereby lysosomal acid lipase (LAL) hydrolyzes cholesterol esters (CE) and triacylglycerols (TAGS) to free cholesterol and free fatty acids, respectively, while the LDLR is recycled back to the cell surface. Both sterol regulatory element-binding protein (SREBP) and proprotein convertase subtilisin/kexin type 9 (PCSK9) regulate intracellular cholesterol via modulation of LDLR expression. (D) Endogenous cholesterol biosynthetic pathway which utilizes 2 acetyl CoA molecules to yield acetoacetyl-CoA via acyl-CoA cholesterol acyltransferase (ACAT). The rate limiting step next converts 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) to mevalonate via HMG-CoA reductase (HMGCR). Subsequent steps include isopentyl pyrophosphate (PP), farnesyl PP to squalene. Final stages will include the cyclization of squalene to ultimately form cholesterol. Cholesterol lowering statins impair HMGCR, while anti-resorptive bisphosphonates inhibit farnesyl disphosphate synthase.

Figure 3.

Implications for bone homeostasis impacting whole body lipid metabolism relative to metabolic competition hypothesis. (Top) During times of active or high bone formation cells of the osteoblast lineage are rapidly utilizing lipids (i.e., fatty acids, triacylglycerol or TAGs, and low density lipoprotein or LDL) and lipid precursors (glucose), drawing them out of the circulation. This action thereby decreases their deposition and accumulation in peripheral cells (tissues) including adipocytes (adipose tissue), hepatocytes (liver), and myocytes (muscle). (Bottom) Alternatively, when bone formation is low, these lipids and lipid substrates are now readily available in the circulation and subsequently become stored in peripheral tissues.