Liver ACOX1 regulates levels of circulating lipids that promote metabolic health through adipose remodeling

Dongliang Lu, Anyuan He, Min Tan, Marguerite Mrad, Amal El Daibani, Donghua Hu, Xuejing Liu, Brian Kleiboeker, Tao Che, Fong-Fu Hsu, Monika Bambouskova, Clay F. Semenkovich and Irfan J. Lodhi ()
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Dongliang Lu: Washington University School of Medicine
Anyuan He: Washington University School of Medicine
Min Tan: Washington University School of Medicine
Marguerite Mrad: Washington University School of Medicine
Amal El Daibani: Washington University School of Medicine
Donghua Hu: Washington University School of Medicine
Xuejing Liu: Washington University School of Medicine
Brian Kleiboeker: Washington University School of Medicine
Tao Che: Washington University School of Medicine
Fong-Fu Hsu: Washington University School of Medicine
Monika Bambouskova: Washington University School of Medicine
Clay F. Semenkovich: Washington University School of Medicine
Irfan J. Lodhi: Washington University School of Medicine

Nature Communications, 2024, vol. 15, issue 1, 1-16

Abstract: Abstract The liver gene expression of the peroxisomal β-oxidation enzyme acyl-coenzyme A oxidase 1 (ACOX1), which catabolizes very long chain fatty acids (VLCFA), increases in the context of obesity, but how this pathway impacts systemic energy metabolism remains unknown. Here, we show that hepatic ACOX1-mediated β-oxidation regulates inter-organ communication involved in metabolic homeostasis. Liver-specific knockout of Acox1 (Acox1-LKO) protects mice from diet-induced obesity, adipose tissue inflammation, and systemic insulin resistance. Serum from Acox1-LKO mice promotes browning in cultured white adipocytes. Global serum lipidomics show increased circulating levels of several species of ω−3 VLCFAs (C24-C28) with previously uncharacterized physiological role that promote browning, mitochondrial biogenesis and Glut4 translocation through activation of the lipid sensor GPR120 in adipocytes. This work identifies hepatic peroxisomal β-oxidation as an important regulator of metabolic homeostasis and suggests that manipulation of ACOX1 or its substrates may treat obesity-associated metabolic disorders.

Date: 2024
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DOI: 10.1038/s41467-024-48471-2

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