cyclic-gmp and Fatty-Liver

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disorder caused by abnormal lipid metabolisms, such as reduced hepatic fatty acid oxidation (FAO), but intracellular control of FAO under physio- and pathological conditions remains largely undefined. Here, we demonstrate that deprivation of Slc7a3a leads to hepatic steatosis in fasted zebrafish as a result of defects in arginine-dependent nitric oxide (NO) synthesis. Fast-induced hepatic steatosis in slc7a3a-null mutants can be rescued by treatments with NO donor, cyclic guanosine monophosphate analog, adenosine-monophosphate-activated protein kinase (AMPK) activator, or peroxisome proliferator-activated receptor alpha (PPAR-α) agonist. In contrast, inhibitors of NO synthases, AMPK, or soluble guanylate cyclase and liver-specifically expressed dominant negatives of peroxisome proliferator-activated receptor-gamma coactivator 1 alpha and PPAR-α are sufficient to induce hepatic steatosis in fasted wild-type larvae. Moreover, knockdown of Slc7a3 in mice or SLC7A3 in human liver cells impaired AMPK-PPAR-α signaling and resulted in lipid accumulation under fasting or glucose starvation, respectively.. These findings have revealed a NO-AMPK-PPAR-α-signaling pathway that is crucial for the control of hepatic FAO in vertebrates.

Topics: Amino Acid Transport Systems, Basic; AMP-Activated Protein Kinases; Animals; Cell Line; Cyclic GMP; Fasting; Fatty Liver; Humans; Lipid Metabolism; Liver; Mice; Mutation; Nitric Oxide; Phenotype; PPAR alpha; Starvation; Transcription Factors; Zebrafish; Zebrafish Proteins

Obesity-associated nonalcoholic fatty liver disease (NAFLD), covering from simple steatosis to nonalcoholic steatohepatitis (NASH), is a common cause of chronic liver disease. Aberrant production of adipocytokines seems to play a main role in most obesity-associated disorders. Changes in adipocytokines in obesity could be mediated by alterations in cyclic GMP (cGMP) homeostasis. The aims of this work were: (1) to study the role of altered cGMP homeostasis in altered adipocytokines in morbid obesity, (2) to assess whether these alterations are different in simple steatosis or NASH, and (3) to assess whether these changes reverse in obese patients after bariatric surgery.. In 47 patients with morbid obesity and 45 control subjects, the levels in blood of adipocytokines, cGMP, nitric oxide (NO) metabolites, and atrial natriuretic peptide (ANP) were studied. Whether weight loss after a bariatric surgery reverses the changes in these parameters was evaluated.. NO metabolites and leptin increase (and adiponectin decreases) similarly in patients with steatosis or NASH, suggesting that these changes are due to morbid obesity and not to liver disease. Inflammation and cGMP homeostasis are affected both by morbid obesity and by liver disease. The increases in interleukin 6 (IL-6), interleukin 18 (IL-18), plasma cGMP, ANP, and the decrease in cGMP in lymphocytes are stronger in patients with NASH than with steatosis. All these changes reverse completely after bariatric surgery and weight loss, except IL-18.. Altered cGMP homeostasis seems to contribute more than inflammation to changes in leptin and adiponectin in morbid obesity.

Topics: Adipokines; Adult; Bariatric Surgery; Body Mass Index; Case-Control Studies; Chronic Disease; Cyclic GMP; Fatty Liver; Female; Homeostasis; Humans; Inflammation; Interleukin-18; Interleukin-6; Leptin; Male; Middle Aged; Non-alcoholic Fatty Liver Disease; Obesity, Morbid

Topics: Adenylyl Cyclases; Cell Membrane; Chronic Disease; Cyclic AMP; Cyclic GMP; Fatty Liver; Hepatitis, Chronic; Humans; Liver; Liver Cirrhosis

The paper concerns studying the participation of cyclic nucleotides in the mechanisms of action of cholecystokinin on gallbladder function in man. Cyclic nucleosides (cAMP and cGMP) were identified by radioimmunoassay in the duodenal contents obtained from men in response to intravenous injection of cholecystokinin. The data obtained suggest that the action of cholecystokinin on gallbladder function in man is mediated via cGMP, whereas cAMP is not implicated in the effect of of cholecystokinin on gallbladder function in man. Disturbances in cyclic nucleotide systems may be viewed in the light of the evidence obtained as a possible pathogenetic factor in the development of gallbladder dyskinesia.

Topics: Bile; Biliary Dyskinesia; Cholecystokinin; Cyclic AMP; Cyclic GMP; Fatty Liver; Humans; Liver; Time Factors