Multiple Myeloma Induced IL-6 Reprograms Lipid Metabolism through a CD36 Dependent Mechanism

Multiple Myeloma (MM) requires a high metabolic turnover to allow for expansion and paraprotein production. MM metabolism is complex relying on various metabolic pathways to fuel its survival including fatty acid (FA) oxidation (1, 2). The liver is a master regulator of fatty acid metabolism and distribution. It also stores FA as lipid droplets during steady state or produces ketone bodies during a starvation state (3). This study aimed to determine whether MM alters FA uptake within the liver and by what mechanism this occurs.

To investigate the role of FA metabolism we used a mouse model of MM (5TGM1 ^(GFP) cells into KaLwRij mice). Analysis of serum from 5TGM1 ^(GFP) engrafted KaLwRij mice showed increased FFA when compared to control animals. RT-qPCR of RNA isolated from liver samples showed a decrease in genes involved in FA uptake and metabolism. These genes included the long chain fatty acid transporter CD36, which belongs to the class B scavenger receptors and is essential for uptake of LCFA in hepatocytes. In vitro modelling showed that primary hepatocytes cultured in conditioned media from 5TGM1 cells had significantly reduced expression of CD36. Furthermore, serum isolated from MM patients (n=6) downregulated CD36 expression in the human hepatocarcinoma cell line, HepG2. These data support the hypothesis that MM induces a factor that alters lipid metabolism in the liver.

To detemine the factor that MM secretes, and which regulates FA uptake in the liver, a cytokine array of the serum from 5TGM1 ^(GFP) engrafted KaLwRij mice was compared to control serum. Pathway analysis revealed interleukin-6 (IL-6) as possible key factor involved in regulating liver FA uptake. In vitro gene expressions analysis of mouse primary hepatocytes revealed that addition of IL-6 to the medium inhibited expression of CD36 and also showed that primary hepatocytes had decreased reliance on FA oxidation when treated with IL-6. Furthermore. 5TGM1 ^(GFP) engrafted KaLwRij mice showed increased serum IL-6 levels compared to controls. Finally, using the IL-6 neutralising antibody, we observed that this blocked CD36 downregulation in HepG2 cultured with MM patient serum.

Here we demonstrate that MM changes FA metabolism in the liver through upregulation of IL-6. Gene expression of FA genes identifies CD36 is down regulated in hepatocytes in response to IL-6. These data suggest that MM is able to redirect FFA away from the liver by down regulating CD36, which mediates FFA uptake in the liver.

References

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• Tirado-Vélez JM, Joumady I, Sáez-Benito A, Cózar-Castellano I, Perdomo G. Inhibition of fatty acid metabolism reduces human myeloma cells proliferation. PLoS One. 2012;7(9):e46484.

• Hodson L, Gunn PJ. The regulation of hepatic fatty acid synthesis and partitioning: the effect of nutritional state. Nat Rev Endocrinol. 2019;15(12):689-700.