Induction of Stearoyl-CoA 9-Desaturase 1 Protects Human Mesenchymal Stromal Cells Against Palmitic Acid-Induced Lipotoxicity and Inflammation

Abstract

In bone diseases such as osteonecrosis and osteoporosis, a shift toward a preferential differentiation of mesenchymal stromal cells (MSC) into adipocytes at the expense of the osteoblastic lineage is described, leading to excessive accumulation of adipocytes in the bone marrow of the patients. The influence of cytokines and adipokines secreted by adipocytes on skeletal health is already well-documented but the impact of free fatty acids release on bone cell biology and viability is an emerging concept. We have previously demonstrated that the saturated fatty acid (SFA) palmitate (Palm) is cytotoxic for human MSC (hMSC) and osteoblasts whereas oleate (Ole), a monounsaturated fatty acid (MUFA), has no toxic effect. Moreover, Ole protects cells against lipotoxicity. Our observations led us to propose that the toxicity of the SFA is not correlated to its intracellular accumulation but could rather be related to the intracellular SFA/MUFA ratio, which finally determines the toxic effect of SFA. Therefore, in the present study, we have investigated the potential protective role of the enzyme stearoyl-CoA 9-desaturase 1 (SCD1) against the deleterious effects of Palm. SCD1 is an enzyme responsible for desaturation of SFA to MUFA; its activation could therefore lead to modifications of the intracellular SFA/MUFA ratio. In the present study, we showed that hMSC express SCD1 and liver X receptors (LXRs), transcription factors regulating SCD1 expression. Human MSC treatment with a LXRs agonist triggered SCD1 expression and drastically reduced Palm-induced cell mortality, caspases 3/7 activation, endoplasmic reticulum stress and inflammation. We also observed that, in the presence of Palm, the LXRs agonist provoked lipid droplets formation, augmented the total cellular neutral lipid content but decreased the SFA/MUFA ratio when compared to Palm treatment alone. Addition of an inhibitor of SCD1 activity abrogated the positive effects of the LXRs agonist, suggesting that SCD1 could play a key role in protecting hMSC against lipotoxicity.

Effect of cis- and trans-Monounsaturated Fatty Acids on Palmitate Toxicity and on Palmitate-induced Accumulation of Ceramides and Diglycerides

“…The outstanding toxicity of saturated FAs is often explained by the reluctance of the cells to process fully saturated DGs, and by the consequent ineffectiveness of channeling the saturated acyl-CoA surplus towards TG synthesis [21]. The theory that unsaturated FAs attenuate palmitate toxicity by facilitating TG synthesis is supported by experimental data obtained in certain cell types, such as CHO cells and primary mouse embryonic fibroblasts [22], mouse myoblasts [23], human mesenchymal stromal cells and osteoblasts [18]. Nevertheless, a palmitate treatment was used in HepG2 hepatocarcinoma cells [17] and controversial data have been published as to the deleterious or protective role of TG deposition in β-cell lipotoxicity [24,25].…”

“…Besides the obvious difference between the cell damage caused by saturated and unsaturated FAs, the potentially protective effect of oleate against palmitate toxicity has also drawn growing attention in the past few years. Simultaneously added oleate alleviated palmitate induced toxicity in various cells, including hepatocytes and hepatoma cells [17], human mesenchymal stromal cells and osteoblasts [18], and also decreased non-alcoholic steatohepatitis (NASH) injury in rats with high fat diets [17]. Most importantly, it has been shown that co-administration of oleate can prevent palmitate-induced activation of the unfolded protein response (UPR) in β-cells [19].…”

Sterculic Acid: The Mechanisms of Action beyond Stearoyl-CoA Desaturase Inhibition and Therapeutic Opportunities in Human Diseases

“…Interestingly, its deficiency is also associated with a narrow eye fissure [22] and skin abnormalities [17]. Recently, it has been demonstrated that SCD1 protects against the palmitate-induced cytotoxic effect in mesenchymal stromal cells and osteoblasts [23]. SCD1 modifies the SFA/MUFA ratio through its catalytic activity and induces caspase 3/ activation, endoplasmic reticulum (ER) stress, and inflammation [23] (Figure 2).…”

“…Recently, it has been demonstrated that SCD1 protects against the palmitate-induced cytotoxic effect in mesenchymal stromal cells and osteoblasts [23]. SCD1 modifies the SFA/MUFA ratio through its catalytic activity and induces caspase 3/ activation, endoplasmic reticulum (ER) stress, and inflammation [23] (Figure 2). SCD1 overexpression is mediated by LXRs, peroxisome proliferator-activated receptors (PPARs), sterol regulatory element-binding proteins (SREBPs), CCAAT/enhancer-binding proteins (C/EBP)α, etc.…”

“…SCD1 overexpression is mediated by LXRs, peroxisome proliferator-activated receptors (PPARs), sterol regulatory element-binding proteins (SREBPs), CCAAT/enhancer-binding proteins (C/EBP)α, etc. [8,23,24]. Curiously, C/EBP also downregulates SCD1 expression in liver and udder during E. coli mastitis and is associated with a SREBP-1 downregulated expression [25].…”