Proteome Dynamics Reveals Pro-inflammatory Remodeling Of Plasma Proteome In A Mouse Model Of Nafld
antiinflammatory properties; Atherosclerosis; Biochemistry & Molecular Biology; fatty liver-disease; gene-expression; HDL; heavy water; high-density-lipoprotein; mass-spectrometry; NAFLD; oxidized phospholipids; ppar-alpha; proteome dynamics; proteomics; rapid method; shotgun; statistical-model
Nonalcoholic fatty liver disease (NAFLD) is associated with an increased risk of cardiovascular disease. Because the liver is the major source of circulatory proteins, it is not surprising that hepatic disease could lead to alterations in the plasma proteome, which are therein implicated in atherosclerosis. The current study used low-density lipoprotein receptor-deficient (LDLR-/-) mice to examine the impact of Western diet (WD)-induced NAFLD on plasma proteome homeostasis. Using a (H2O)-H-2-metabolic labeling method, we found that a WD led to a proinflammatory distribution of circulatory proteins analyzed in apoB-depleted plasma, which was attributed to an increased production. The fractional turnover rates of short-lived proteins that are implicated in stress-response, lipid metabolism, and transport functions were significantly increased with WD (P < 0.05). Pathway analyses revealed that alterations in plasma proteome dynamics were related to the suppression of hepatic PPAR alpha, which was confirmed based on reduced gene and protein expression of PPAR alpha in mice fed a WD. These changes were associated with similar to 4-fold increase (P < 0.0001) in the proinflammatory property of apoB-depleted plasma. In conclusion, the proteome dynamics method reveals proinflammatory remodeling of the plasma proteome relevant to liver disease. The approach used herein may provide a useful metric of in vivo liver function and better enable studies of novel therapies surrounding NAFLD and other diseases.
Li L; Bebek G; Previs S F; Smith J D; Sadygov R G; McCullough A J; Willard B; Kasumov T
Journal of Proteome Research
2016
2016-09
Journal Article or Conference Abstract Publication
<a href="http://doi.org/10.1021/acs.jproteome.6b00601" target="_blank" rel="noreferrer noopener">10.1021/acs.jproteome.6b00601</a>
Decreasing Cb1 Receptor Signaling In Kupffer Cells Improves Insulin Sensitivity In Obese Mice
adiponectin receptors; adipose-tissue; CB1 receptors; disruption; endocannabinoid system; Endocrinology & Metabolism; fatty liver-disease; Inflammation; Insulin resistance; Kupffer cells; macrophage polarization; nf-kappa-b; nonalcoholic steatohepatitis; protein-2; reactive oxygen; siRNA; targeted; uncoupling
Objective: Obesity-induced accumulation of ectopic fat in the liver is thought to contribute to the development of insulin resistance, and increased activity of hepatic CB1R has been shown to promote both processes. However, lipid accumulation in liver can be experimentally dissociated from insulin resistance under certain conditions, suggesting the involvement of additional mechanisms. Obesity is also associated with pro-inflammatory changes which, in turn, can promote insulin resistance. Kupffer cells (KCs), the liver's resident macrophages, are the major source of pro-inflammatory cytokines in the liver, such as TNF-alpha, which has been shown to inhibit insulin signaling in multiple cell types, including hepatocytes. Here, we sought to identify the role of CB1R in KCs in obesity-induced hepatic insulin resistance. Methods: We used intravenously administered beta-D-glucan-encapsulated siRNA to knock-down CB1R gene expression selectively in KCs. Results: We demonstrate that a robust knock-down of the expression of Cnr1, the gene encoding CB1R, results in improved glucose tolerance and insulin sensitivity in diet-induced obese mice, without affecting hepatic lipid content or body weight. Moreover, Cnr1 knock-down in KCs was associated with a shift from pro-inflammatory M1 to anti-inflammatory M2 cytokine profile and improved insulin signaling as reflected by increased insulin-induced Akt phosphorylation. Conclusion: These findings suggest that CB1R expressed in KCs plays a critical role in obesity-related hepatic insulin resistance via a pro inflammatory mechanism. Published by Elsevier GmbH.
Jourdan T; Nicoloro S M; Zhou Z; Shen Y F; Liu J; Coffey N J; Cinar R; Godlewski G; Gao B; Aouadi M; Czech M P; Kunos G
Molecular Metabolism
2017
2017-11
Journal Article or Conference Abstract Publication
<a href="http://doi.org/10.1016/j.molmet.2017.08.011" target="_blank" rel="noreferrer noopener">10.1016/j.molmet.2017.08.011</a>
Hepatic Neuregulin 4 Signaling Defines An Endocrine Checkpoint For Steatosis-to-nash Progression
alpha-induced apoptosis; association; brown; fatty liver-disease; Inflammation; mice; necroptosis; necrotic cell-death; nonalcoholic steatohepatitis; pathogenesis; Research & Experimental Medicine
Nonalcoholic steatohepatitis (NASH) is characterized by progressive liver injury, inflammation, and fibrosis; however, the mechanisms that govern the transition from hepatic steatosis, which is relatively benign, to NASH remain poorly defined. Neuregulin 4 (Nrg4) is an adipose tissue-enriched endocrine factor that elicits beneficial metabolic effects in obesity. Here, we show that Nrg4 is a key component of an endocrine checkpoint that preserves hepatocyte health and counters diet-induced NASH in mice. Nrg4 deficiency accelerated liver injury, fibrosis, inflammation, and cell death in a mouse model of NASH. In contrast, transgenic expression of Nrg4 in adipose tissue alleviated diet-induced NASH. Nrg4 attenuated hepatocyte death in a cell-autonomous manner by blocking ubiquitination and proteasomal degradation of c-FLIPL, a negative regulator of cell death. Adeno-associated virus-mediated (AAV-mediated) rescue of hepatic c-FLIPL expression in Nrg4-deficent mice functionally restored the brake for steatosis to NASH transition. Thus, hepatic Nrg4 signaling serves as an endocrine checkpoint for steatosis-to-NASH progression by activating a cytoprotective pathway to counter stress-induced liver injury.
Guo L; Zhang P; Chen Z M; Xia H J; Li S M; Zhang Y Q; Kobberup S; Zou W P; Lin J D
Journal of Clinical Investigation
2017
2017-12
Journal Article or Conference Abstract Publication
<a href="http://doi.org/10.1172/jci96324" target="_blank" rel="noreferrer noopener">10.1172/jci96324</a>
FARNESOID X RECEPTOR: ACTING THROUGH BILE ACIDS TO TREAT METABOLIC DISORDERS
fatty liver-disease; foam-cell formation; growth-factor receptor; heterodimer partner; insulin-resistance; nonalcoholic steatohepatitis; orphan nuclear receptor; Pharmacology & Pharmacy; primary rat hepatocytes; protein-kinase-c; regulatory cascade; small
The famesoid X receptor (FXR) is a member of the nuclear receptor superfamily and plays an important role in maintaining bile acid, lipid and glucose homeostasis. Bile acids are endogenous ligands for FXR. However, bile acids may also activate pathways independent of FXR. The development of specific FXR agonists has provided important insights into the role of FXR in metabolism. Recent data have demonstrated that FXR is a therapeutic target for the treatment of certain metabolic disorders. This review will focus on recent advances in the role of FXR in metabolic disease.
Zhang Y
Drugs of the Future
2010
2010-08
Journal Article
<a href="http://doi.org/10.1358/dof.2010.35.8.1520865" target="_blank" rel="noreferrer noopener">10.1358/dof.2010.35.8.1520865</a>
Role of Nuclear Receptors in Lipid Dysfunction and Obesity-Related Diseases
bile-acid-homeostasis; carbohydrate-metabolism; constitutive androstane receptor; estrogen sulfotransferase; farnesoid X receptor; fatty liver-disease; glucose-homeostasis; heterodimer partner; insulin sensitivity; Pharmacology & Pharmacy; small; type-2 diabetes-mellitus
This article is a report on a symposium sponsored by the American Society for Pharmacology and Experimental Therapeutics and held at the Experimental Biology 12 meeting in San Diego, CA. The presentations discussed the roles of a number of nuclear receptors in regulating glucose and lipid homeostasis, the pathophysiology of obesity-related disease states, and the promise associated with targeting their activities to treat these diseases. While many of these receptors (in particular, constitutive androstane receptor and pregnane X receptor) and their target enzymes have been thought of as regulators of drug and xenobiotic metabolism, this symposium highlighted the advances made in our understanding of the endogenous functions of these receptors. Similarly, as we gain a better understanding of the mechanisms underlying bile acid signaling pathways in the regulation of body weight and glucose homeostasis, we see the importance of using complementary approaches to elucidate this fascinating network of pathways. The observation that some receptors, like the farnesoid X receptor, can function in a tissue-specific manner via well defined mechanisms has important clinical implications, particularly in the treatment of liver diseases. Finally, the novel findings that agents that selectively activate estrogen receptor beta can effectively inhibit weight gain in a high-fat diet model of obesity identifies a new role for this member of the steroid superfamily. Taken together, the significant findings reported during this symposium illustrate the promise associated with targeting a number of nuclear receptors for the development of new therapies to treat obesity and other metabolic disorders.
Swanson H I; Wada T; Xie W; Renga B; Zampella A; Distrutti E; Fiorucci S; Kong B; Thomas A M; Guo G L; Narayanan R; Yepuru M; Dalton J T; Chiang J Y L
Drug Metabolism and Disposition
2013
2013-01
Journal Article
<a href="http://doi.org/10.1124/dmd.112.048694" target="_blank" rel="noreferrer noopener">10.1124/dmd.112.048694</a>
Understanding Bile Acid Signaling in Diabetes: From Pathophysiology to Therapeutic Targets.
BILE acids; Bile acids and salts; cholesterol 7-alpha-hydroxylase; Cytoplasmic and Nuclear; Endocrinology & Metabolism; FARNESOID X receptor; farnesoid-x-receptor; FATTY liver; fatty liver-disease; G protein coupled receptors; G-protein-coupled; Gastrointestinal microbiome; growth-factor 19; gut microbiota; hepatic steatosis; improves insulin sensitivity; liver disease; metabolic; Non-alcoholic fatty; Non-alcoholic Fatty Liver Disease; nuclear; receptor; Receptors; serum fgf21 levels; syndrome
Diabetes and obesity have reached an epidemic status worldwide. Diabetes increases the risk for cardiovascular disease and nonalcoholic fatty liver disease. Primary bile acids are synthesized in hepatocytes and are transformed to secondary bile acids in the intestine by gut bacteria. Bile acids are nutrient sensors and metabolic integrators that regulate lipid, glucose, and energy homeostasis by activating nuclear farnesoid X receptor and membrane Takeda G protein-coupled receptor 5. Bile acids control gut bacteria overgrowth, species population, and protect the integrity of the intestinal barrier. Gut bacteria, in turn, control circulating bile acid composition and pool size. Dysregulation of bile acid homeostasis and dysbiosis causes diabetes and obesity. Targeting bile acid signaling and the gut microbiome have therapeutic potential for treating diabetes, obesity, and non-alcoholic fatty liver disease. [ABSTRACT FROM AUTHOR]
Ferrell Jessica M; Chiang John Y L
Diabetes & Metabolism Journal
2019
2019-06
<a href="http://doi.org/10.4093/dmj.2019.0043" target="_blank" rel="noreferrer noopener">10.4093/dmj.2019.0043</a>