Partnership of PGC-1α and HNF4α in the Regulation of Lipoprotein Metabolism

Abstract

Peroxisome proliferator-activated receptor ␥ coactivator-1␣ (PGC-1␣) is a transcriptional coactivator involved in several aspects of energy metabolism. It is induced or activated under different stimuli in a highly tissue-specific manner and subsequently partners with certain transcription factors in those tissues to execute various biological programs. In the fasted liver, PGC-1␣ is induced and interacts with hepatocyte nuclear factor 4␣ (HNF4␣) and other transcription factors to activate gluconeogenesis and increase hepatic glucose output. Given the broad spectrum of liver genes responsive to HNF4␣, we sought to determine those that were specifically targeted by the combination of PGC-1␣ and HNF4␣. Coexpression of these two molecules in murine stem cells reveals a high induction of mRNA for apolipoproteins A-IV and C-II. Forced expression of PGC-1␣ in mouse and human hepatoma cells increases the mRNA of a subset of apolipoproteins implicated in very low density lipoprotein and triglyceride metabolism, including apolipoproteins A-IV, C-II, and C-III. Coactivation of the apoC-III/ A-IV promoter region by PGC-1␣ occurs through a highly conserved HNF4␣ response element, the loss of which completely abolishes activation by PGC-1␣ and HNF4␣. Adenoviral infusion of PGC-1␣ into live mice increases hepatic expression of apolipoproteins A-IV, C-II, and C-III and increases serum and very low density lipoprotein triglyceride levels. Conversely, knock down of PGC-1␣ in vivo causes a decrease in both apolipoprotein expression and serum triglyceride levels. These data point to a crucial role for the PGC-1␣/HNF4␣ partnership in hepatic lipoprotein metabolism.The liver is central to systemic nutrient metabolism. It regulates both catabolic and anabolic processes that maintain proper blood levels of protein, carbohydrate, and lipid. The liver responds to blood-borne hormones and neurotransmitters, executing biological programs to ensure that the energy demands of peripheral tissues are satisfied. Many of these programs exert metabolic changes through the activation or induction of specific transcription factors, which in turn increase the expression of key enzymes or other downstream regulators.The peroxisome proliferator-activated receptor ␥ (PPAR␥) 4 coactivator-1␣ (PGC-1␣) (1) has emerged as an important regulator of several liver functions. It positively regulates hepatic heme biosynthesis and links fasting to acute attacks of porphyria (2). PGC-1␣ induces CYP7A1, the rate-limiting enzyme of bile acid synthesis (3-5). It also partners with liver X receptor ␣ and farnesoid X receptor in modulating cholesterol and triglyceride metabolism (6, 7). In the hepatic response to fasting, PGC-1␣ coordinates the induction of genes involved in gluconeogenesis, fatty acid oxidation, and ketogenesis (8, 9). Its coactivation of the liver-enriched transcription factors HNF4␣ and FOXO1, as well as the glucocorticoid receptor, results in the induction of gluconeogenic enzymes and increased hepatic glucose output (10, 11). The functional loss...

Transcriptional regulation of apolipoprotein A-IV by the transcription factor CREBH

“…PPAR ␥ coactivator-1 ␣ (PGC1 ␣ ) did not further activate the 5.9 kb Apoa4-luciferase reporter, despite it being known as a coactivator of HNF-4 ␣ ( 16, 25 ). HNF-4 ␣ failed to activate the 0.9 kb Apoa4-luciferase reporter, consistent with the requirement for apoCIII enhancer in HNF-4 ␣ -mediated apoA-IV activation ( 25 ). CREBH(N) cotransfection dramatically increased the luciferase activity of both 5.9 kb Apoa4-luciferase and 0.9 kb Apoa4-luciferase reporters by more than 1,000-fold ( Fig.…”

“…2A ). Earlier studies demonstrated that nuclear hormone receptors such as HNF-4 ␣ and estrogen receptor ␣ (ERR ␣ ) activate apoA-IV transcription through the apoC-III enhancer, which is located near the Apoc3 gene ( 16,(23)(24)(25)(26). To investigate the roles of different transcription factors in Apoa4 transcription, luciferase reporter constructs containing 5.9 kb or 0.9 kb fragments of Apoa4 promoter were generated.…”

Carbohydrate Metabolism Is Perturbed in Peroxisome-deficient Hepatocytes Due to Mitochondrial Dysfunction, AMP-activated Protein Kinase (AMPK) Activation, and Peroxisome Proliferator-activated Receptor γ Coactivator 1α (PGC-1α) Suppression

“…PGC-1␣ is a central regulator of hepatic gluconeogenesis and induces the enzymes PEPCK and G-6-Pase via coactivation of FOXO1, HNF4␣, and the glucocorticoid receptor (43)(44)(45)(46). Reduced mRNA expression of PGC-1␣ was confirmed by qRT-PCR in fed and fasted mice (Fig.…”

“…Remarkably, SIRT1 protein levels were also reduced, and Gcn5 transcripts were increased concomitantly. PGC-1␣ is a key driving factor of gluconeogenesis by coactivating FOXO1, HNF4␣ and the glucocorticoid receptor (43)(44)(45)(46). We showed that reduced PGC-1␣ activity may contribute to impaired gluconeogenesis in L-Pex5 Ϫ/Ϫ mice.…”

Mechanisms of lifespan extension and preventive effects of calorie restriction on tumor development: Possible link between central neuroendocrine system and peripheral metabolic adaptation

“…HNF-4α is an important transcription factor in glucose and lipid metabolism in the liver and forms a complex with PGC-1α 31,32) . Levels of the HNF-4α/PGC-1α complex are increased in the liver of CR animals, and putative HNF-4RE-containing genes are up-regulated in pro-longevity contexts 4) .…”