A role for long-chain acyl-CoA synthetase-4 (ACSL4) in diet-induced phospholipid remodeling and obesity-associated adipocyte dysfunction

Authors: KILLION, ELIZABETH - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; REEVES, ANDREW - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; EL AZZOUNY, MAHMOUD - University Of Michigan; YAN, QING-WU - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; SURUJON, DEFNE - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; GRIFFIN, JOHN - Friedman School Of Nutrition; BOWMAN, THOMAS - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; WANG, CHUNYAN - Sanford And Burnham Medical Research Institute; MATTHAN, NIRUPA - Friedman School Of Nutrition; KLETT, ERIC - University Of North Carolina; KONG, DONG - University Of California; Newman, John; HAN, XIANLIN - Sanford And Burnham Medical Research Institute; LEE, MI-JEONG - Boston University Medical School; COLEMAN, ROSALIND - University Of North Carolina; GREENBERG, ANDREW - Friedman School Of Nutrition

Submitted to: Molecular Metabolism
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 1/16/2018
Publication Date: 1/31/2018
Citation: Killion, E.A., Reeves, A.R., El Azzouny, M.A., Yan, Q., Surujon, D., Griffin, J.D., Bowman, T.A., Wang, C., Matthan, N.R., Klett, E.L., Kong, D., Newman, J.W., Han, X., Lee, M., Coleman, R.A., Greenberg, A.S. 2018. A role for long-chain acyl-CoA synthetase-4 (ACSL4) in diet-induced phospholipid remodeling and obesity-associated adipocyte dysfunction. Molecular Metabolism. 9:43-46. https://doi.org/10.1016/j.molmet.2018.01.012.
DOI: https://doi.org/10.1016/j.molmet.2018.01.012

Interpretive Summary: Diet-induced obesity (DIO) disrupts the regulation of fatty acid (FA) metabolism in adipocytes. The enzyme responsible for activating long chain FAs so that they can be inserted into membranes is called long-chain acyl-CoA synthetase-4 (ACSL4). It has been hypothesized that ACSL4 modulates the metabolic fate of polyunsaturated FAs (PUFA), including arachidonic acid (AA), but the actions of ACSL4 within a living organism are unknown. Using genetic techniques, we removed the ACSL4 enzyme from the adipose tissue in a unique strain of mice (Ad-KO), and loss of this gene protected these mice from DIO when fed a high fat diet (HFD). Adipose cells from Ad-KO mice fed the HFD reduced AA incorporation into phospholipids (PL), free AA, and levels of the AA lipid peroxidation product 4-hydroxynonenal (4-HNE). Consistent with the known actions of 4-HNE, adipocytes from Ad-KO mice had reduced p53 activation and increased adipocyte oxygen consumption. These studies are the first to elucidate the in vivo ACSL4-dependent regulation of AA incorporation into PL and the downstream effects on DIO-associated dysfunctions.

Technical Abstract: Regulation of fatty acid (FA) metabolism is central to adipocyte dysfunction during diet-induced obesity (DIO). Long-chain acyl-CoA synthetase-4 (ACSL4) has been hypothesized to modulate the metabolic fates of polyunsaturated FA (PUFA), including arachidonic acid (AA), but the in vivo actions of ACSL4 are unknown. When we fed a high fat diet (HFD) to mice with adipocyte specific ablation of ACSL4 (Ad-KO), they were protected against DIO and metabolic dysfunction. Adipocytes from Ad-KO mice fed HFD had reduced incorporation of AA into phospholipids (PL), free AA, and levels of the AA lipid peroxidation product 4-hydroxynonenal (4-HNE). Consistent with the known actions of 4-HNE, adipocytes from Ad-KO mice had reduced p53 activation and increased adipocyte oxygen consumption. These studies are the first to elucidate ACSL4’s in vivo actions to regulate incorporation of AA into PL and downstream effects on DIO-associated adipocyte dysfunction.