Unraveling the Secrets of the Double Bond
The etymology of “kine” refers to any kind of bovine (cow)? So, a lipokine must refer to a fat bovine, right? Not quite.
The term lipokine was first coined in 2008 in a Cell publication titled “Identification of a Lipokine, a Lipid Hormone Linking Adipose Tissue to Systemic Metabolism” by Gokhan S. Hotamisligil, et. al. In this publication, Hotamisligil uses the term lipokine to refer to a fatty acid capable of modulating lipid metabolism via a chaperone effect. Now, lipokine more broadly refers to lipid-controlling hormones. Some examples include palmitoleic acid discovered by Hotamisligil, which improves cell sensitivity to insulin and reduces fat accumulation in the liver, and fatty acid esters of hydroxy fatty acids (FAHFAs) which are formed in adipose tissue and improves glucose tolerance and reduces tissue inflammation (Kahn, et. al., 2014).
More recently, another lipokine has been identified linked to stress responses and stress signaling.
PI (18:1/18:1) - a lipid linking cell stress and cell death:
Cell death is a necessary process in biology as it assists in the removal of unwanted cells. If a cell evades death or even lives longer than it should, the result could be the development or exacerbation of disease. Fatty acids are known to play a role in cell metabolism and stress signaling.
Excessive amounts of saturated fatty acids (SFAs) lead to lipotoxic stress while polyunsaturated acids (PUFAs) can cause membranes to be more susceptible to oxidative stress. Our cells have evolved to sense and adapt to stressful environments. Some of these mechanisms cause cytosolic components to be degraded to provide the energy necessary for stress-protective mechanisms such as converting SFAs to monounsaturated fatty acids (MUFAs). The SFA/MUFA ratio is influenced by several parameters including diet, but the cell can adjust this ratio using stearoyl-CoA desaturases (SCDs) that introduce a cis-double bond into SFA-CoA.
Pinpointing how SCD effects and regulates stress-signaling has proven to be challenging. However, recently, Koeberle, et.al. 2022 identified at least one of the lipids responsible for the interplay between SCDs and stress-signaling – 1,2-dioleoyl-sn-glycero-3-phospho-(1’-myo-inositol) or PI (18:1/18:1). The study found that PI (18:1/18:1), which is derived from SCD1, plays several roles in stress-related mechanisms inside the cell, including:
- Interference with unfolded protein response (UPR) which is how the cell maintains the balance of protein folding in the ER
- Interference with autophagy
- Inhibits the activation of p38 MAPK via MKK3/6
- Promotes maintenance of cell morphology
- Supports cell proliferation
- Inhibits the induction of programmed cell death
Aside from discovering that PI (18:1/18:1) acts as a lipid metabolism modulator in stress-signaling, they also found that it was either upregulated or downregulated depending on the stress environment. In stress-tolerant systems such as aged immune cells, chemoresistant cancer cells, and tumors, PI (18:1/18:1) was found to be upregulated. In systems that are stress-sensitive (i.e., aged stem cells, infected bone under lipotoxic stress), PI (18:1/18:1) was found to be downregulated.
Identifying PIs as a key player in stress-signaling could provide scientists with a viable target for treatment of stress-related diseases such as metabolic syndrome or cancer. And one of the things that METLIN helps accomplish.