Liver-specific loss of long chain acyl-CoA synthetase-1 decreases triacylglycerol synthesis and beta-oxidation and alters phospholipid fatty acid composition.
In mammals, a family of five acyl-CoA synthetases (ACSLs), each the product of a separate gene, activates long chain fatty acids to form acyl-CoAs. Because the ACSL isoforms have overlapping preferences for fatty acid chain length and saturation and are expressed in many of the same tissues, the individual function of each isoform has remained uncertain. Thus, we constructed a mouse model with a liver-specific knock-out of ACSL1, a major ACSL isoform in liver. Eliminating ACSL1 in liver resulted in a 50% decrease in total hepatic ACSL activity and a 25-35% decrease in long chain acyl-CoA content. Although the content of triacylglycerol was unchanged in Acsl1(L)(-/-) liver after mice were fed either low or high fat diets, in isolated primary hepatocytes the absence of ACSL1 diminished the incorporation of [(14)C]oleate into triacylglycerol. Further, small but consistent increases were observed in the percentage of 16:0 in phosphatidylcholine and phosphatidylethanolamine and of 18:1 in phosphatidylethanolamine and lysophosphatidylcholine, whereas concomitant decreases were seen in 18:0 in phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, and lysophosphatidylcholine. In addition, decreases in long chain acylcarnitine content and diminished production of acid-soluble metabolites from [(14)C]oleate suggested that hepatic ACSL1 is important for mitochondrial beta-oxidation of long chain fatty acids. Because the Acsl1(L)(-/-) mice were not protected from developing either high fat diet-induced hepatic steatosis or insulin resistance, our study suggests that lowering the content of hepatic acyl-CoA without a concomitant decrease in triacylglycerol and other lipid intermediates is insufficient to protect against hepatic insulin resistance.
Li
Lei O
LO
Department of Nutrition, University of North Carolina, Chapel Hill, North Carolina 27599.
Ellis
Jessica M
JM
Department of Nutrition, University of North Carolina, Chapel Hill, North Carolina 27599.
Paich
Heather A
HA
Department of Nutrition, University of North Carolina, Chapel Hill, North Carolina 27599.
Wang
Shuli
S
Department of Nutrition, University of North Carolina, Chapel Hill, North Carolina 27599.
Gong
Nan
N
Department of Nutrition, University of North Carolina, Chapel Hill, North Carolina 27599.
Altshuller
George
G
Department of Genetics, University of North Carolina, Chapel Hill, North Carolina 27599.
Thresher
Randy J
RJ
Department of Genetics, University of North Carolina, Chapel Hill, North Carolina 27599.
Koves
Timothy R
TR
Department of Medicine, Duke University, Durham, North Carolina 27710.
Watkins
Steven M
SM
Lipomics Technologies, Inc., West Sacramento, California 95691.
Muoio
Deborah M
DM
Department of Medicine, Duke University, Durham, North Carolina 27710.
Cline
Gary W
GW
Department of Internal Medicine and Cellular and Molecular Physiology, Howard Hughes Medical Institute, Yale University, New Haven, Connecticut 06510.
Shulman
Gerald I
GI
Department of Internal Medicine and Cellular and Molecular Physiology, Howard Hughes Medical Institute, Yale University, New Haven, Connecticut 06510.
Coleman
Rosalind A
RA
Department of Nutrition, University of North Carolina, Chapel Hill, North Carolina 27599. Electronic address: rcoleman@unc.edu.
D000818:Animals; D002478:Cells, Cultured; D003066:Coenzyme A Ligases / Q000235:genetics / Q000378:metabolism*; D004032:Diet; D005215:Fasting; D005227:Fatty Acids / Q000737:chemistry* / Q000378:metabolism; D018390:Gene Targeting; D005951:Glucose Tolerance Test; D022781:Hepatocytes / Q000166:cytology / Q000378:metabolism; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010084:Oxidation-Reduction; D010743:Phospholipids / Q000737:chemistry* / Q000378:metabolism; D014280:Triglycerides / Q000096:biosynthesis*
D005227:Fatty Acids; D007527:Isoenzymes; D010743:Phospholipids; D014280:Triglycerides; D003066:Coenzyme A Ligases