Compensatory increase in fatty acid synthesis in adipose tissue of mice with conditional deficiency of SCAP in liver.
The escort protein SCAP transports SREBPs from ER to Golgi where the active domains are released to activate genes for fatty acid (FA) and cholesterol synthesis. Mice with conditional SCAP deficiency in liver (L-Scap-) manifest marked reductions in hepatic lipid synthesis. Here, we show that the decreased FA synthesis in liver is balanced by an equal increase in nonhepatic tissues, primarily adipose tissue. Extrahepatic synthesis of FAs preserves adipose mass, even when L-Scap- mice consume a fat-free diet. This compensatory response disappears upon fasting, implicating a role for insulin, the major hormonal activator of FA synthesis. This response is mediated by an insulin-dependent increase in adipocyte SREBP-1c and its target mRNAs. In epididymal fat of L-Scap- mice, phosphorylated Akt, Glut-4 mRNA, and glucose uptake are also increased, indicating insulin hypersensitivity. Plasma VLDL triglycerides are dramatically reduced in L-Scap- mice, underscoring the benefits of synthesizing FAs in fat rather than liver.
Kuriyama
Hiroshi
H
Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
Liang
Guosheng
G
Engelking
Luke J
LJ
Horton
Jay D
JD
Goldstein
Joseph L
JL
Brown
Michael S
MS
D000273:Adipose Tissue / Q000378:metabolism*; D000818:Animals; D001835:Body Weight; D002784:Cholesterol / Q000378:metabolism; D003847:Deoxyglucose / Q000493:pharmacokinetics; D015536:Down-Regulation; D005227:Fatty Acids / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism; D005951:Glucose Tolerance Test; D015151:Immunoblotting; D007328:Insulin / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins; D008099:Liver / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins / Q000096:biosynthesis* / Q000172:deficiency*; D051379:Mice; D008822:Mice, Transgenic; D009929:Organ Size; D010641:Phenotype; D010766:Phosphorylation; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D014280:Triglycerides / Q000378:metabolism; D015854:Up-Regulation
D005227:Fatty Acids; D007328:Insulin; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D012333:RNA, Messenger; C102196:SREBP cleavage-activating protein; D014280:Triglycerides; D002784:Cholesterol; D003847:Deoxyglucose; D005947:Glucose