Hypoglycemic effect of Chrysanthemum morifolium extract on alloxan-induced diabetic mice is associated with peroxisome proliferator-activated receptor α/γ-mediated hepatic glycogen synthesis

2017 ◽  
Vol 15 (1) ◽  
pp. 81-86 ◽  
Author(s):  
Xiang Shang ◽  
Zeng-Yan Zhu ◽  
Feng Wang ◽  
Jin-Cheng Liu ◽  
Jiang-Yun Liu ◽  
...  
Keyword(s):  
Glycogen Synthesis ◽  
Chrysanthemum Morifolium ◽  
Hypoglycemic Effect ◽  
Hepatic Glycogen ◽  
Peroxisome Proliferator ◽  
Diabetic Mice ◽  
Peroxisome Proliferator Activated Receptor

scholarly journals Peroxisome-proliferator-activated receptor-α (PPARα) deficiency leads to dysregulation of hepatic lipid and carbohydrate metabolism by fatty acids and insulin

2002 ◽  
Vol 364 (2) ◽  
pp. 361-368 ◽  
Author(s):  
Mary C. SUGDEN ◽  
Karen BULMER ◽  
Geoffrey F. GIBBONS ◽  
Brian L. KNIGHT ◽  
Mark J. HOLNESS
Keyword(s):  
Fatty Acids ◽  
Fatty Acid ◽  
Carbohydrate Metabolism ◽  
Plasma Insulin ◽  
Hepatic Glycogen ◽  
Peroxisome Proliferator ◽  
Hepatic Lipogenesis ◽  
Wild Type ◽  
Peroxisome Proliferator Activated Receptor ◽  
Hepatic Lipid

The aim of the present study was to determine whether peroxisome-proliferator-activated receptor-α (PPARα) deficiency disrupts the normal regulation of triacylglycerol (TAG) accumulation, hepatic lipogenesis and glycogenesis by fatty acids and insulin using PPARα-null mice. In wild-type mice, hepatic TAG concentrations increased (P<0.01) with fasting (24h), with substantial reversal after refeeding (6h). Hepatic TAG levels in fed PPARα-null mice were 2.4-fold higher than in the wild-type (P<0.05), increased with fasting, but remained elevated after refeeding. PPARα deficiency also impaired hepatic glycogen repletion (P<0.001), despite normal insulin and glucose levels after refeeding. Higher levels of plasma insulin were required to support similar levels of hepatic lipogenesis de novo (3H2O incorporation) in the PPARα-null mice compared with the wild-type. This difference was reflected by corresponding changes in the relationship between plasma insulin and the mRNA expression of the lipogenic transcription factor sterol-regulatory-element-binding protein-1c, and that of one of its known targets, fatty acid synthase. In wild-type mice, hepatic pyruvate dehydrogenase kinase (PDK) 4 protein expression (a downstream marker of altered fatty acid catabolism) increased (P<0.01) in response to fasting, with suppression (P<0.001) by refeeding. Although PDK4 up-regulation after fasting was halved by PPARα deficiency, PDK4 suppression after refeeding was attenuated. In summary, PPARα deficiency leads to accumulation of hepatic TAG and elicits dysregulation of hepatic lipid and carbohydrate metabolism, emphasizing the importance of precise control of lipid oxidation for hepatic fuel homoeostasis.

scholarly journals Peroxisome proliferator-activated receptor-δ induces insulin-induced gene-1 and suppresses hepatic lipogenesis in obese diabetic mice

Hepatology ◽  
2008 ◽  
Vol 48 (2) ◽  
pp. 432-441 ◽  
Author(s):  
Xiaomei Qin ◽  
Xuefen Xie ◽  
Yanbo Fan ◽  
Jianwei Tian ◽  
Youfei Guan ◽  
...  
Keyword(s):  
Peroxisome Proliferator ◽  
Diabetic Mice ◽  
Hepatic Lipogenesis ◽  
Peroxisome Proliferator Activated Receptor

Abstract 13671: GSK-3α Directly Regulates Lipid Metabolism Through Obesity-linked Phosphorylation of PPARα

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Michinari Nakamura ◽  
Peiyong Zhai ◽  
Tong Liu ◽  
Hong Li ◽  
Junichi Sadoshima
Keyword(s):  
Lipid Metabolism ◽  
Cardiac Dysfunction ◽  
Lipid Accumulation ◽  
Glycogen Synthase ◽  
Body Weight Gain ◽  
Glycogen Synthesis ◽  
Mass Spectrometry Analysis ◽  
Peroxisome Proliferator ◽  
Obese Mice ◽  
Peroxisome Proliferator Activated Receptor

Obesity impairs lipid metabolism and leads to cardiac dysfunction, where peroxisome proliferator-activated receptor α (PPARα) serves as a key regulator of lipid metabolism. Glycogen synthase kinase-3α (GSK-3α), a serine-threonine kinase, is markedly upregulated in the heart of obese mice, suppressing glycogen synthesis. However, the functional significance of upregulated GSK-3α in lipid metabolism remains unknown. Here we show that GSK-3α directly upregulates lipid metabolism and aggravates cardiac lipotoxicity in obesity. GSK-3α activity was enhanced by palmitic acid (PA) in the nucleus in cardiomyocytes (CMs), and knockdown of GSK-3α suppressed PA-induced activation of PPARα. GSK-3α, but not GSK-3β, directly interacted with PPARα. Mass spectrometry analysis revealed that GSK-3α phosphorylates PPARα at Ser280, located in the ligand binding domain. A PPARα phospho-mimicking mutant (PPARα-S280D) exhibited an increase in both the interaction of PPARα with RXR and its DNA binding, enhancing PPARα activity and stimulating expression of lipid metabolism-related genes, including Cpt1b, CD36 and PDHK4, in CMs. High-fat diet (HFD)-fed mice displayed increased GSK-3α activity and PPARα phosphorylation in the heart. Cardiac-specific haploinsufficiency of GSK-3α normalized HFD-induced lipid accumulation (Oil Red O staining), abnormally enhanced palmitate oxidation (0.82 fold, p<0.05), cardiac hypertrophy and diastolic dysfunction (0.36 fold in EDPVR, p<0.05) without affecting body weight gain or food intake. While adenovirus-mediated overexpression of PPARα in the heart exacerbated HFD-induced lipid dysregulation and cardiac dysfunction, that of PPARα phospho-resistant mutant (PPARα-S280A) failed to facilitate lipid metabolism and cardiac dysfunction in the presence of a HFD. Notably, a PPARα ligand, fenofibrate, allosterically inhibited PPARα phosphorylation in obese mice by interfering with the interaction between GSK-3α and PPARα, and improved HFD-induced lipid accumulation and cardiac dysfunction. These data show that GSK-3α directly regulates lipid metabolism through Ser280 phosphorylation of PPARα, and that its phosphorylation could be a novel therapeutic target for obesity-related cardiac dysfunction.

scholarly journals CREBH Maintains Circadian Glucose Homeostasis by Regulating Hepatic Glycogenolysis and Gluconeogenesis

2017 ◽  
Vol 37 (14) ◽  
Author(s):  
Hyunbae Kim ◽  
Ze Zheng ◽  
Paul D. Walker ◽  
Gregory Kapatos ◽  
Kezhong Zhang
Keyword(s):  
Blood Glucose ◽  
Glucose Homeostasis ◽  
Phosphoenolpyruvate Carboxykinase ◽  
Liver Glycogen ◽  
Glycogen Storage ◽  
Hepatic Glycogen ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Glucose Levels ◽  
Blood Glucose Levels

ABSTRACT Cyclic AMP-responsive element binding protein, hepatocyte specific (CREBH), is a liver-enriched, endoplasmic reticulum-tethered transcription factor known to regulate the hepatic acute-phase response and lipid homeostasis. In this study, we demonstrate that CREBH functions as a circadian transcriptional regulator that plays major roles in maintaining glucose homeostasis. The proteolytic cleavage and posttranslational acetylation modification of CREBH are regulated by the circadian clock. Functionally, CREBH is required in order to maintain circadian homeostasis of hepatic glycogen storage and blood glucose levels. CREBH regulates the rhythmic expression of the genes encoding the rate-limiting enzymes for glycogenolysis and gluconeogenesis, including liver glycogen phosphorylase (PYGL), phosphoenolpyruvate carboxykinase 1 (PCK1), and the glucose-6-phosphatase catalytic subunit (G6PC). CREBH interacts with peroxisome proliferator-activated receptor α (PPARα) to synergize its transcriptional activities in hepatic gluconeogenesis. The acetylation of CREBH at lysine residue 294 controls CREBH-PPARα interaction and synergy in regulating hepatic glucose metabolism in mice. CREBH deficiency leads to reduced blood glucose levels but increases hepatic glycogen levels during the daytime or upon fasting. In summary, our studies revealed that CREBH functions as a key metabolic regulator that controls glucose homeostasis across the circadian cycle or under metabolic stress.

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