Liver specific inactivation of carboxylesterase 3/triacylglycerol hydrolase decreases blood lipids without causing severe steatosis in mice.
Carboxylesterase 3/triacylglycerol hydrolase (Ces3/TGH) participates in hepatic very low-density lipoprotein (VLDL) assembly and in adipose tissue basal lipolysis. Global ablation of Ces3/Tgh expression decreases serum triacylglycerol (TG) and nonesterified fatty acid levels and improves insulin sensitivity. To understand the tissue-specific role of Ces3/TGH in lipid and glucose homeostasis, we generated mice with a liver-specific deletion of Ces3/Tgh expression (L-TGH knockout [KO]). Elimination of hepatic Ces3/Tgh expression dramatically decreased plasma VLDL TG and VLDL cholesterol concentrations but only moderately increased liver TG levels in mice fed a standard chow diet. Significantly reduced plasma TG and cholesterol without hepatic steatosis were also observed in L-TGH KO mice challenged with a high-fat, high-cholesterol diet. L-TGH KO mice presented with increased plasma ketone bodies and hepatic fatty acid oxidation. Intrahepatic TG in L-TGH KO mice was stored in significantly smaller lipid droplets. Augmented hepatic TG levels in chow-fed L-TGH KO mice did not affect glucose tolerance or glucose production from hepatocytes, but impaired insulin tolerance was observed in female mice.


CONCLUSIONS
Our data suggest that ablation of hepatic Ces3/Tgh expression decreases plasma lipid levels without causing severe hepatic steatosis.
Group on Molecular and Cell Biology of Lipids, University of Alberta, Edmonton, Alberta, Canada.
Jihong
J
Lian
Enhui
E
Wei
Shu Pei
SP
Wang
Ariel D
AD
Quiroga
Lena
L
Li
Alba
A
Di Pardo
Jelske
J
van der Veen
Simonetta
S
Sipione
Grant A
GA
Mitchell
Richard
R
Lehner
D000818:Animals; D002791:Cholesterol, Dietary / Q000008:administration & dosage; D015243:Cholesterol, VLDL / Q000097:blood* / Q000378:metabolism; D004041:Dietary Fats / Q000008:administration & dosage; D005227:Fatty Acids / Q000378:metabolism; D005234:Fatty Liver / Q000378:metabolism; D005260:Female; D005947:Glucose / Q000096:biosynthesis; D005951:Glucose Tolerance Test; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance; D007657:Ketone Bodies / Q000097:blood; D008049:Lipase / Q000172:deficiency* / Q000235:genetics; D008079:Lipoproteins, VLDL / Q000097:blood* / Q000378:metabolism; D008099:Liver / Q000201:enzymology* / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D015398:Signal Transduction; D014280:Triglycerides / Q000097:blood* / Q000378:metabolism
D002791:Cholesterol, Dietary; D015243:Cholesterol, VLDL; D004041:Dietary Fats; D005227:Fatty Acids; D007328:Insulin; D007657:Ketone Bodies; D008079:Lipoproteins, VLDL; D014280:Triglycerides; C030106:very low density lipoprotein triglyceride; D008049:Lipase; D005947:Glucose