Hepatic VLDL production in ob/ob mice is not stimulated by massive de novo lipogenesis but is less sensitive to the suppressive effects of insulin.
Type 2 diabetes in humans is associated with increased de novo lipogenesis (DNL), increased fatty acid (FA) fluxes, decreased FA oxidation, and hepatic steatosis. In this condition, VLDL production is increased and resistant to suppressive effects of insulin. The relationships between hepatic FA metabolism, steatosis, and VLDL production are incompletely understood. We investigated VLDL-triglyceride and -apolipoprotein (apo)-B production in relation to DNL and insulin sensitivity in female ob/ob mice. Hepatic triglyceride (5-fold) and cholesteryl ester (15-fold) contents were increased in ob/ob mice compared with lean controls. Hepatic DNL was increased approximately 10-fold in ob/ob mice, whereas hepatic cholesterol synthesis was not affected. Basal rates of hepatic VLDL-triglyceride and -apoB100 production were similar between the groups. Hyperinsulinemic clamping reduced VLDL-triglyceride and -apoB100 production rates by approximately 60% and approximately 75%, respectively, in lean mice but only by approximately 20% and approximately 20%, respectively, in ob/ob mice. No differences in hepatic expression of genes encoding apoB and microsomal triglyceride transfer protein were found. Hepatic expression and protein phosphorylation of insulin receptor and insulin receptor substrate isoforms were reduced in ob/ob mice. Thus, strongly induced hepatic DNL is not associated with increased VLDL production in ob/ob mice, possibly related to differential hepatic zonation of apoB synthesis (periportal) and lipid accumulation (perivenous) and/or relatively low rates of cholesterogenesis. Insulin is unable to effectively suppress VLDL-triglyceride production in ob/ob mice, presumably because of impaired insulin signaling.
Wiegman
Coen H
CH
University Institute for Drug Exploration, Center for Liver, Digestive and Metabolic Diseases, Department of Pediatrics, University Hospital Groningen, Hanzeplein 1, 9700 GB Groningen, the Netherlands.
Bandsma
Robert H J
RH
Ouwens
Margriet
M
van der Sluijs
Fjodor H
FH
Havinga
Rick
R
Boer
Theo
T
Reijngoud
Dirk-Jan
DJ
Romijn
Johannes A
JA
Kuipers
Folkert
F
D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D053299:Apolipoprotein B-100; D001055:Apolipoproteins B / Q000096:biosynthesis / Q000187:drug effects; D001483:Base Sequence; D002784:Cholesterol / Q000096:biosynthesis; D002788:Cholesterol Esters / Q000096:biosynthesis; D017931:DNA Primers; D005786:Gene Expression Regulation; D006946:Hyperinsulinism / Q000378:metabolism; D007328:Insulin / Q000494:pharmacology*; D007700:Kinetics; D008055:Lipids / Q000096:biosynthesis*; D008079:Lipoproteins, VLDL / Q000096:biosynthesis / Q000187:drug effects / Q000235:genetics*; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D008820:Mice, Obese; D015345:Oligonucleotide Probes; D012016:Reference Values; D014280:Triglycerides / Q000097:blood
D053299:Apolipoprotein B-100; D001055:Apolipoproteins B; D002788:Cholesterol Esters; D017931:DNA Primers; D007328:Insulin; D008055:Lipids; D008079:Lipoproteins, VLDL; D015345:Oligonucleotide Probes; D014280:Triglycerides; D002784:Cholesterol