Beyond thermoregulation: metabolic function of cetacean blubber in migrating bowhead and beluga whales.
*Lipid Metabolism; Adipose Tissue/*metabolism; Aging/metabolism; Amino Acid Sequence; Animals; Base Sequence; Beluga Whale/*physiology; Blubber; Body Temperature Regulation; Bowhead whale; Bowhead Whale/*physiology; Development; Female; Humans; Inbred C57BL; Leptin; Leptin/genetics; Leptin/genetics/metabolism; Lipase/genetics; Long-Evans; Male; Metabolic activity; Mice; Rats; Receptors; Seasons
The processes of lipid deposition and utilization, via the gene leptin (Lep), are poorly understood in taxa with varying degrees of adipose storage. This study examines how these systems may have adapted in marine aquatic environments inhabited by cetaceans. Bowhead (Balaena mysticetus) and beluga whales (Delphinapterus leucas) are ideal study animals-they possess large subcutaneous adipose stores (blubber) and undergo bi-annual migrations concurrent with variations in food availability. To answer long-standing questions regarding how (or if) energy and lipid utilization adapted to aquatic stressors, we quantified variations in gene transcripts critical to lipid metabolism related to season, age, and blubber depth. We predicted leptin tertiary structure conservation and assessed inter-specific variations in Lep transcript numbers between bowheads and other mammals. Our study is the first to identify seasonal and age-related variations in Lep and lipolysis in these cetaceans. While Lep transcripts and protein oscillate with season in adult bowheads reminiscent of hibernating mammals, transcript levels reach up to 10 times higher in bowheads than any other mammal. Data from immature bowheads are consistent with the hypothesis that short baleen inhibits efficient feeding. Lipolysis transcripts also indicate young Fall bowheads and those sampled during Spring months limit energy utilization. These novel data from rarely examined species expand the existing knowledge and offer unique insight into how the regulation of Lep and lipolysis has adapted to permit seasonal deposition and maintain vital blubber stores.
Ball H C; Londraville R L; Prokop J W; George John C; Suydam R S; Vinyard C; Thewissen J G M; Duff R J
Journal of comparative physiology. B, Biochemical, systemic, and environmental physiology
2017
2017-01
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1007/s00360-016-1029-6" target="_blank" rel="noreferrer noopener">10.1007/s00360-016-1029-6</a>
Nuclear receptor regulation of lipid metabolism: potential therapeutics for dyslipidemia, diabetes, and chronic heart and liver diseases.
Humans; Animals; Chronic Disease; *Lipid Metabolism; Hypoglycemic Agents/therapeutic use; Diabetes Mellitus/drug therapy/metabolism; Dyslipidemias/drug therapy/metabolism; Heart Diseases/*drug therapy/metabolism; Hypolipidemic Agents/therapeutic use; Liver Diseases/*drug therapy/metabolism; Metabolic Diseases/*drug therapy/metabolism; Receptors; Cytoplasmic and Nuclear/*metabolism
Lipids are essential components of biological membranes, fuel molecules and metabolic regulators that control cellular functions, metabolism and homeostasis. The liver plays a central role in regulating lipid metabolism and whole body lipid homeostasis. Sterols, bile acids and fatty acids are the endogenous ligands of the liver orphan receptor, farnesoid X receptor, peroxisome proliferator-activated receptor, vitamin D receptor, constitutive androstane receptor and pregnane X receptor. These metabolic receptors coordinately regulate lipid, glucose, energy and drug metabolism. Alteration of lipid homeostasis causes dyslipidemia, which is a major risk factor contributing to atherosclerotic cardiovascular diseases, diabetes, obesity and liver diseases. Advances in the understanding of the mechanisms of nuclear receptor regulation of lipid homeostasis have provided an opportunity to investigate potential therapeutic drugs targeted to nuclear receptors. This could be useful for the treatment of diabetes, and cardiovascular and chronic liver diseases.
Chiang John Y L
Current opinion in investigational drugs (London, England : 2000)
2005
2005-10
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
PXR induces CYP27A1 and regulates cholesterol metabolism in the intestine.
*Lipid Metabolism; ATP Binding Cassette Transporter; ATP Binding Cassette Transporter 1; ATP-Binding Cassette Transporters/genetics; Base Sequence; Cell Line; Cholestanetriol 26-Monooxygenase/*metabolism; Cholesterol; Cholesterol/*metabolism; Fluorinated; Genes; Genetic/drug effects; Genetic/genetics; HDL/metabolism; Hepatocytes/drug effects/enzymology/metabolism; Humans; Hydrocarbons; Hydroxycholesterols/metabolism/pharmacology; Intestinal Mucosa/metabolism; Intestines/cytology/drug effects/enzymology; Member 1; Messenger/genetics/metabolism; Molecular Sequence Data; Pregnane X Receptor; Promoter Regions; Receptors; Reporter; Response Elements/genetics; Rifampin/pharmacology; RNA; Steroid/*metabolism; Subfamily G; Sulfonamides/pharmacology; Transcription; Up-Regulation/drug effects
Mitochondrial sterol 27-hydroxylase (CYP27A1) catalyzes oxidative cleavage of the sterol side chain in the bile acid biosynthetic pathway in the liver and
Li Tiangang; Chen Wenling; Chiang John Y L
Journal of lipid research
2007
2007-02
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1194/jlr.M600282-JLR200" target="_blank" rel="noreferrer noopener">10.1194/jlr.M600282-JLR200</a>
Carboxylesterase 2 prevents liver steatosis by modulating lipolysis, endoplasmic reticulum stress, and lipogenesis and is regulated by hepatocyte nuclear factor 4 alpha in mice.
*Lipid Metabolism; Adiposity; Animals; Carboxylesterase/*metabolism; Carboxylic Ester Hydrolases/genetics/*metabolism; Diabetes Mellitus; Diet; Endoplasmic Reticulum Stress; Energy Metabolism; Experimental/enzymology; Gene Knockdown Techniques; Glucose Tolerance Test; Glucose/metabolism; Hepatocyte Nuclear Factor 4/*metabolism; High-Fat/adverse effects; Homeostasis; Humans; Inbred C57BL; Lipogenesis; Lipolysis; Liver/enzymology; Male; Mice; Non-alcoholic Fatty Liver Disease/*etiology/metabolism; Obesity/enzymology/etiology; Sterol Regulatory Element Binding Protein 1/metabolism
UNLABELLED: Nonalcoholic fatty liver disease (NAFLD) is a common liver disease that ranges from simple steatosis to nonalcoholic steatohepatitis (NASH). So far, the underlying mechanism remains poorly understood. Here, we show that hepatic carboxylesterase 2 (CES2) is markedly reduced in NASH patients, diabetic db/db mice, and high-fat diet (HFD)-fed mice. Restoration of hepatic CES2 expression in db/db or HFD-fed mice markedly ameliorates liver steatosis and insulin resistance. In contrast, knockdown of hepatic CES2 causes liver steatosis and damage in chow- or Western diet-fed C57BL/6 mice. Mechanistically, we demonstrate that CES2 has triglyceride hydrolase activity. As a result, gain of hepatic CES2 function increases fatty acid oxidation and inhibits lipogenesis, whereas loss of hepatic CES2 stimulates lipogenesis by inducing endoplasmic reticulum stress. We further show that loss of hepatic CES2 stimulates lipogenesis in a sterol regulatory element-binding protein 1 (SREBP-1)-dependent manner. Finally, we show that hepatocyte nuclear factor 4 alpha (HNF-4alpha) plays a key role in controlling hepatic CES2 expression in diabetes, obesity, or NASH. CONCLUSION: CES2 plays a protective role in development of NAFLD. Targeting the
Li Yuanyuan; Zalzala Munaf; Jadhav Kavita; Xu Yang; Kasumov Takhar; Yin Liya; Zhang Yanqiao
Hepatology (Baltimore, Md.)
2016
2016-06
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1002/hep.28472" target="_blank" rel="noreferrer noopener">10.1002/hep.28472</a>
Farnesoid X receptor induces Takeda G-protein receptor 5 cross-talk to regulate bile acid synthesis and hepatic metabolism.
*bile acid; *bile acid metabolism; *FXR; *Gene Expression Regulation; *GLP-1; *lipid metabolism; *liver metabolism; *non-alcoholic fatty liver disease; *obesity; *TGR5; *type 2 diabetes; Animals; Bile Acids and Salts/*biosynthesis/genetics; Cytoplasmic and Nuclear/genetics/*metabolism; Dietary Fats; G-Protein-Coupled/genetics/*metabolism; Glucagon-Like Peptide 1/genetics/metabolism; Glucose/metabolism; Knockout; Lipid Metabolism; Liver/*metabolism; Mice; Obesity/genetics/*metabolism/pathology; Receptors
The bile acid-activated receptors, nuclear farnesoid X receptor (FXR) and the membrane Takeda G-protein receptor 5 (TGR5), are known to improve glucose and insulin sensitivity in obese and diabetic mice. However, the metabolic roles of these two receptors and the underlying mechanisms are incompletely understood. Here, we studied the effects of the dual FXR and TGR5 agonist INT-767 on hepatic bile acid synthesis and intestinal secretion of glucagon-like peptide-1 (GLP-1) in wild-type, Fxr(-/-), and Tgr5(-/-) mice. INT-767 efficaciously stimulated intracellular Ca(2+) levels, cAMP activity, and GLP-1 secretion and improved glucose and lipid metabolism more than did the FXR-selective obeticholic acid and
Pathak Preeti; Liu Hailiang; Boehme Shannon; Xie Cen; Krausz Kristopher W; Gonzalez Frank; Chiang John Y L
The Journal of biological chemistry
2017
2017-06
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1074/jbc.M117.784322" target="_blank" rel="noreferrer noopener">10.1074/jbc.M117.784322</a>
Hepatic carboxylesterase 1 is essential for both normal and farnesoid X receptor-controlled lipid homeostasis.
*Homeostasis; *Lipid Metabolism; Animals; Carboxylic Ester Hydrolases/*physiology; Cholesterol/blood; Cytoplasmic and Nuclear/*physiology; Fatty Acids/metabolism; Inbred C57BL; Lipogenesis; Liver/*enzymology; Mice; Receptors; Sterol Regulatory Element Binding Protein 1/physiology; Triglycerides/metabolism
UNLABELLED: Nonalcoholic fatty liver disease (NAFLD) is one of the major health concerns worldwide. Farnesoid X receptor (FXR) is considered a therapeutic target for treatment of NAFLD. However, the mechanism by which activation of FXR lowers hepatic triglyceride (TG) levels remains unknown. Here we investigated the role of hepatic carboxylesterase 1 (CES1) in regulating both normal and FXR-controlled lipid homeostasis. Overexpression of hepatic CES1 lowered hepatic TG and plasma glucose levels in both wild-type and diabetic mice. In contrast, knockdown of hepatic CES1 increased hepatic TG and plasma cholesterol levels. These effects likely resulted from the TG hydrolase activity of CES1, with subsequent changes in fatty acid oxidation and/or de novo lipogenesis. Activation of FXR induced hepatic CES1, and reduced the levels of hepatic and plasma TG as well as plasma cholesterol in a CES1-dependent manner. CONCLUSION: Hepatic CES1 plays a critical role in regulating both lipid and carbohydrate metabolism and FXR-controlled lipid homeostasis.
Xu Jiesi; Li Yuanyuan; Chen Wei-Dong; Xu Yang; Yin Liya; Ge Xuemei; Jadhav Kavita; Adorini Luciano; Zhang Yanqiao
Hepatology (Baltimore, Md.)
2014
2014-05
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1002/hep.26714" target="_blank" rel="noreferrer noopener">10.1002/hep.26714</a>