Sensitivity of lipid metabolism and insulin signaling to genetic alterations in hepatic peroxisome proliferator-activated receptor-gamma coactivator-1alpha expression.
OBJECTIVE
The peroxisome proliferator-activated receptor-gamma coactivator (PGC)-1 family of transcriptional coactivators controls hepatic function by modulating the expression of key metabolic enzymes. Hepatic gain of function and complete genetic ablation of PGC-1alpha show that this coactivator is important for activating the programs of gluconeogenesis, fatty acid oxidation, oxidative phosphorylation, and lipid secretion during times of nutrient deprivation. However, how moderate changes in PGC-1alpha activity affect metabolism and energy homeostasis has yet to be determined.


METHODS
To identify key metabolic pathways that may be physiologically relevant in the context of reduced hepatic PGC-1alpha levels, we used the Cre/Lox system to create mice heterozygous for PGC-1alpha specifically within the liver (LH mice).


RESULTS
These mice showed fasting hepatic steatosis and diminished ketogenesis associated with decreased expression of genes involved in mitochondrial beta-oxidation. LH mice also exhibited high circulating levels of triglyceride that correlated with increased expression of genes involved in triglyceride-rich lipoprotein assembly. Concomitant with defects in lipid metabolism, hepatic insulin resistance was observed both in LH mice fed a high-fat diet as well as in primary hepatocytes.


CONCLUSIONS
These data highlight both the dose-dependent and long-term effects of reducing hepatic PGC-1alpha levels, underlining the importance of tightly regulated PGC-1alpha expression in the maintenance of lipid homeostasis and glucose metabolism.
Dana-Farber Cancer Institute and Department of Cell Biology, Harvard Medical School, Boston, MA, USA.
Jennifer L
JL
Estall
Mario
M
Kahn
Marcus P
MP
Cooper
Ffolliott Martin
FM
Fisher
Michele K
MK
Wu
Dina
D
Laznik
Lishu
L
Qu
David E
DE
Cohen
Gerald I
GI
Shulman
Bruce M
BM
Spiegelman
D000273:Adipose Tissue / Q000033:anatomy & histology; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D001823:Body Composition; D018929:Cell Culture Techniques; D003433:Crosses, Genetic; D005234:Fatty Liver / Q000235:genetics; D005260:Female; D005786:Gene Expression Regulation; D022781:Hepatocytes / Q000166:cytology / Q000502:physiology*; D006706:Homeostasis; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance; D019426:Integrases / Q000235:genetics; D007659:Ketones / Q000097:blood; D008055:Lipids / Q000097:blood / Q000502:physiology; D008099:Liver / Q000033:anatomy & histology / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D034741:RNA, Small Interfering / Q000235:genetics; D015534:Trans-Activators / Q000235:genetics*; D014157:Transcription Factors; D014280:Triglycerides / Q000097:blood*
D001786:Blood Glucose; D007328:Insulin; D007659:Ketones; D008055:Lipids; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D034741:RNA, Small Interfering; D015534:Trans-Activators; D014157:Transcription Factors; D014280:Triglycerides; C045073:Cre recombinase; D019426:Integrases