Signal Transduction Mechanisms of Alcoholic Fatty Liver Disease: Emer ging Role of Lipin-1.
Humans; Animals; AMP-Activated Protein Kinases/metabolism; Signal Transduction; Lipid Metabolism; Fatty Liver; Liver/metabolism; lipid metabolism; alcoholic fatty liver disease; inflammation; Lipin-1; signal transduction; transcriptional regulators; Phosphatidate Phosphatase/*metabolism; Inflammation/metabolism; Ethanol/chemistry/*metabolism; Sirtuin 1/metabolism; Alcoholic/*metabolism/pathology
Lipin-1, a mammalian phosphatidic acid phosphatase (PAP), is a bi-functional molecule involved in various signaling pathways via its function as a PAP enzyme in the triglyceride synthesis pathway and in the nucleus as a transcriptional co-regulator. In the liver, lipin-1 is known to play a vital role in controlling the lipid metabolism and inflammation process at multiple regulatory levels. Alcoholic fatty liver disease (AFLD) is one of the earliest forms of liver injury and approximately 8-20% of patients with simple steatosis can develop into more severe forms of liver injury, including steatohepatitis, fibrosis/ cirrhosis, and eventually hepatocellular carcinoma (HCC). The signal transduction mechanisms for alcohol-induced detrimental effects in liver involves alteration of complex and multiple signaling pathways largely governed by a central and upstream signaling system, namely, sirtuin 1 (SIRT1)-AMP activated kinase (AMPK) axis. Emerging evidence suggests a pivotal role of lipin-1 as a crucial downstream regulator of
You Min; Jogasuria Alvin; Lee Kwangwon; Wu Jiashin; Zhang Yanqiao; Lee Yoon-Kwang; Sadana Prabodh
Current molecular pharmacology
2017
1905-7
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/10.2174/1874467208666150817112109" target="_blank" rel="noreferrer noopener">10.2174/1874467208666150817112109</a>
The anti-parkinsonian drug zonisamide reduces neuroinflammation: Role of microglial Nav 1.6.
Female; Humans; Male; Animals; Mice; Aged; *gp91(phox); *Microglia; *MPTP; *Na(v)1.6; *Neuroinflammation; *Parkinson's disease; *TNF-alpha; *Voltage-gated sodium channels; *Zonisamide; Inflammation/metabolism; Neuroprotective Agents/pharmacology; Antiparkinson Agents/*pharmacology; Inbred C57BL; Microglia/drug effects/*metabolism; NAV1.6 Voltage-Gated Sodium Channel/*biosynthesis; Parkinsonian Disorders/*metabolism/pathology; Zonisamide/*pharmacology
Parkinson's disease (PD), the second most common age-related progressive neurodegenerative disorder, is characterized by dopamine depletion and the loss of dopaminergic (DA) neurons with accompanying neuroinflammation. Zonisamide is an-anti-convulsant drug that has recently been shown to improve clinical symptoms of PD through its inhibition of monoamine oxidase B (MAO-B). However, zonisamide has additional targets, including voltage-gated sodium channels (Nav), which may contribute to its reported neuroprotective role in preclinical models of PD. Here, we report that Nav1.6 is highly expressed in microglia of post-mortem PD brain and of mice treated with the parkinsonism-inducing neurotoxin MPTP. Administration of zonisamide (20mg/kg, i.p. every 4hx3) following a single injection of MPTP (12.5mg/kg, s.c.) reduced microglial Nav 1.6 and microglial activation in the striatum, as indicated by Iba-1 staining and mRNA expression of F4/80. MPTP increased the levels of the pro-inflammatory cytokine TNF-alpha and gp91(phox), and this was significantly reduced by zonisamide. Together, these findings suggest that zonisamide may reduce neuroinflammation through the down-regulation of microglial Nav 1.6. Thus, in addition to its effects on parkinsonian symptoms through inhibition of MAO-B, zonisamide may have disease modifying potential through the inhibition of Nav 1.6 and neuroinflammation.
Hossain Muhammad M; Weig Blair; Reuhl Kenneth; Gearing Marla; Wu Long-Jun; Richardson Jason R
Experimental neurology
2018
2018-10
<a href="http://doi.org/10.1016/j.expneurol.2018.07.005" target="_blank" rel="noreferrer noopener">10.1016/j.expneurol.2018.07.005</a>
Bile acid metabolism and signaling.
Animals; Bile Acids and Salts/*metabolism/therapeutic use; Biliary Tract Diseases/metabolism; Cholesterol/metabolism; Cytoplasmic and Nuclear/metabolism; Enterohepatic Circulation/physiology; Feedback; G-Protein-Coupled/metabolism; Homeostasis/physiology; Humans; Inflammation/metabolism; Liver/metabolism; Physiological/physiology; Receptors; Signal Transduction/*physiology
Bile acids are important physiological agents for intestinal nutrient absorption and biliary secretion of lipids, toxic metabolites, and xenobiotics. Bile acids also are signaling molecules and metabolic regulators that activate nuclear receptors and G protein-coupled receptor (GPCR) signaling to regulate hepatic lipid, glucose, and energy homeostasis and maintain metabolic homeostasis. Conversion of cholesterol to bile acids is critical for maintaining cholesterol homeostasis and preventing accumulation of cholesterol, triglycerides, and toxic metabolites, and injury in the liver and other organs. Enterohepatic circulation of bile acids from the liver to intestine and back to the liver plays a central role in nutrient absorption and distribution, and metabolic regulation and homeostasis. This physiological process is regulated by a complex membrane transport system in the liver and intestine regulated by nuclear receptors. Toxic bile acids may cause inflammation, apoptosis, and cell death. On the other hand, bile acid-activated nuclear and GPCR signaling protects against inflammation in liver, intestine, and macrophages. Disorders in bile acid metabolism cause cholestatic liver diseases, dyslipidemia, fatty liver diseases, cardiovascular diseases, and diabetes. Bile acids, bile acid derivatives, and bile acid sequestrants are therapeutic agents for treating chronic liver diseases, obesity, and diabetes in humans.
Chiang John Y L
Comprehensive Physiology
2013
2013-07
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/cphy.c120023" target="_blank" rel="noreferrer noopener">10.1002/cphy.c120023</a>