Format

Send to

Choose Destination
Nat Chem Biol. 2018 Nov;14(11):1021-1031. doi: 10.1038/s41589-018-0132-2. Epub 2018 Oct 16.

Enzyme promiscuity drives branched-chain fatty acid synthesis in adipose tissues.

Author information

1
Department of Bioengineering, University of California, San Diego, La Jolla, CA, USA.
2
Departments of Chemistry, Molecular and Cell Biology, and Nutritional Science and Toxicology, University of California, Berkeley, Berkeley, CA, USA.
3
Nomis Center for Immunobiology and Microbial Pathogenesis, The Salk Institute for Biological Studies, La Jolla, CA, USA.
4
Division of Biological Sciences, University of California at San Diego, La Jolla, CA, USA.
5
Division of Endocrinology, Division of Developmental Biology, Cincinnati Children's Hospital Research Foundation, Cincinnati, OH, USA.
6
Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
7
Division of Pediatric Endocrinology, Department of Pediatrics, University of California at San Diego, La Jolla, CA, USA.
8
Virginia San Diego Healthcare System, San Diego, CA, USA.
9
Division of Endocrinology & Metabolism, Department of Medicine, University of California at San Diego, La Jolla, CA, USA.
10
Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA, USA.
11
NAFLD Research Center, Division of Gastroenterology, Department of Medicine, University of California at San Diego, La Jolla, CA, USA.
12
Department of Bioengineering, University of California, San Diego, La Jolla, CA, USA. cmetallo@ucsd.edu.
13
Moores Cancer Center, University of California, San Diego, La Jolla, CA, USA. cmetallo@ucsd.edu.
14
Diabetes Research Center, University of California, San Diego, La Jolla, CA, USA. cmetallo@ucsd.edu.

Abstract

Fatty acid synthase (FASN) predominantly generates straight-chain fatty acids using acetyl-CoA as the initiating substrate. However, monomethyl branched-chain fatty acids (mmBCFAs) are also present in mammals but are thought to be primarily diet derived. Here we demonstrate that mmBCFAs are de novo synthesized via mitochondrial BCAA catabolism, exported to the cytosol by adipose-specific expression of carnitine acetyltransferase (CrAT), and elongated by FASN. Brown fat exhibits the highest BCAA catabolic and mmBCFA synthesis fluxes, whereas these lipids are largely absent from liver and brain. mmBCFA synthesis is also sustained in the absence of microbiota. We identify hypoxia as a potent suppressor of BCAA catabolism that decreases mmBCFA synthesis in obese adipose tissue, such that mmBCFAs are significantly decreased in obese animals. These results identify adipose tissue mmBCFA synthesis as a novel link between BCAA metabolism and lipogenesis, highlighting roles for CrAT and FASN promiscuity influencing acyl-chain diversity in the lipidome.

PMID:
30327559
PMCID:
PMC6245668
[Available on 2019-04-16]
DOI:
10.1038/s41589-018-0132-2
Free full text

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for eScholarship, California Digital Library, University of California
Loading ...
Support Center