Department of Biochemistry, The University of Texas Health Science Center at San Antonio, TX, United States.
Department of Biochemistry, The University of Texas Health Science Center at San Antonio, TX, United States; The Sam and Ann Barshop Institute for Longevity and Aging Studies, The University of Texas Health Science Center at San Antonio, TX, United States.
Biochem Biophys Res Commun. 2014 Jul 18;450(1):777-81. doi: 10.1016/j.bbrc.2014.06.063. Epub 2014 Jun 21.
Aging is associated with the accumulation of ectopic lipid resulting in the inhibition of normal organ function, a phenomenon known as lipotoxicity. Within the bone marrow microenvironment, elevation in fatty acid levels may produce an increase in osteoclast activity and a decrease in osteoblast number and function, thus contributing to age-related osteoporosis. However, little is known about lipotoxic mechanisms in intramembraneous bone. Previously we reported that the long chain saturated fatty acid palmitate inhibited the expression of the osteogenic markers RUNX2 and osteocalcin in fetal rat calvarial cell (FRC) cultures. Moreover, the acetyl CoA carboxylase inhibitor TOFA blocked the inhibitory effect of palmitate on expression of these two markers. In the current study we have extended these observations to show that palmitate inhibits spontaneous mineralized bone formation in FRC cultures in association with reduced mRNA expression of RUNX2, alkaline phosphatase, osteocalcin, and bone sialoprotein and reduced alkaline phosphatase activity. The effects of palmitate on osteogenic marker expression were inhibited by TOFA. Palmitate also inhibited the mRNA expression of fatty acid synthase and PPARγ in FRC cultures, and as with osteogenic markers, this effect was inhibited by TOFA. Palmitate had no effect on FRC cell proliferation or apoptosis, but inhibited BMP-7-induced alkaline phosphatase activity. We conclude that palmitate accumulation may lead to lipotoxic effects on osteoblast differentiation and mineralization and that increases in fatty acid oxidation may help to prevent these lipotoxic effects.
衰老是与异位脂质的积累相关的，导致正常器官功能的抑制，这种现象被称为脂毒性。在骨髓微环境中，脂肪酸水平的升高可能导致破骨细胞活性增加和成骨细胞数量和功能减少，从而导致与年龄相关的骨质疏松症。然而，关于膜内骨的脂毒性机制知之甚少。我们之前曾报道过，长链饱和脂肪酸棕榈酸可抑制胎鼠颅骨细胞（FRC）培养物中成骨标志物 RUNX2 和骨钙素的表达。此外，乙酰辅酶 A 羧化酶抑制剂 TOFA 可阻断棕榈酸对这两种标志物表达的抑制作用。在本研究中，我们进一步观察到，棕榈酸可抑制 FRC 培养物中自发矿化骨形成，与 RUNX2、碱性磷酸酶、骨钙素和骨涎蛋白的 mRNA 表达减少以及碱性磷酸酶活性降低有关。TOFA 可抑制棕榈酸对成骨标志物表达的影响。棕榈酸还可抑制 FRC 培养物中脂肪酸合酶和 PPARγ 的 mRNA 表达，与成骨标志物一样，TOFA 也可抑制这种作用。棕榈酸对 FRC 细胞增殖或凋亡没有影响，但可抑制 BMP-7 诱导的碱性磷酸酶活性。我们得出结论，棕榈酸的积累可能导致成骨细胞分化和矿化的脂毒性作用，而增加脂肪酸氧化可能有助于预防这些脂毒性作用。
