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Nathan Goodyear

Glucocorticoids plus N-Acetylcysteine in Severe Alcoholic Hepatitis | NEJM - 0 views

www.nejm.org/...NEJMoa1101214

NAC N-acetylcysteine bilirubin liver hepatitis alcoholic hepatitis

shared by Nathan Goodyear on 20 Aug 18 - No Cached
  • Nathan Goodyear on 20 Aug 18
     
    NAC benefits short-term survival in alcoholic hepatitis, including a drop in bilirubin.
Nathan Goodyear

Metabolic endotoxemia: a molecular link between obesity and cardiovascular risk - 0 views

jme.endocrinology-journals.org/...R51.full

metabolic endotoxemia obesity insulin resistance cardiovascular disease LPS inflammation

shared by Nathan Goodyear on 04 Aug 14 - No Cached
  • Weight gain has been associated with a higher gut permeability
  • a high-fat diet promotes LPS absorption
  • higher concentrations of fatty acids impair intestinal barrier integrity
  • ...37 more annotations...
  • The starting point for innate immunity activation is the recognition of conserved structures of bacteria, viruses, and fungal components through pattern-recognition receptors
  • TLRs are PRRs that recognize microbe-associated molecular patterns
  • TLRs are transmembrane proteins containing extracellular domains rich in leucine repeat sequences and a cytosolic domain homologous to the IL1 receptor intracellular domain
  • The major proinflammatory mediators produced by the TLR4 activation in response to endotoxin (LPS) are TNFα, IL1β and IL6, which are also elevated in obese and insulin-resistant patients
  • Obesity, high-fat diet, diabetes, and NAFLD are associated with higher gut permeability leading to metabolic endotoxemia.
  • Probiotics, prebiotics, and antibiotic treatment can reduce LPS absorption
  • LPS promotes hepatic insulin resistance, hypertriglyceridemia, hepatic triglyceride accumulation, and secretion of pro-inflammatory cytokines promoting the progression of fatty liver disease.
  • In the endothelium, LPS induces the expression of pro-inflammatory, chemotactic, and adhesion molecules, which promotes atherosclerosis development and progression.
  • In the adipose tissue, LPS induces adipogenesis, insulin resistance, macrophage infiltration, oxidative stress, and release of pro-inflammatory cytokines and chemokines.
  • the gut microbiota has been recently proposed to be an environmental factor involved in the control of body weight and energy homeostasis by modulating plasma LPS levels
  • dietary fats alone might not be sufficient to cause overweight and obesity, suggesting that a bacterially related factor might be responsible for high-fat diet-induced obesity.
  • This was accompanied in high-fat-fed mice by a change in gut microbiota composition, with reduction in Bifidobacterium and Eubacterium spp.
  • n humans, it was also shown that meals with high-fat and high-carbohydrate content (fast-food style western diet) were able to decrease bifidobacteria levels and increase intestinal permeability and LPS concentrations
  • it was demonstrated that, more than the fat amount, its composition was a critical modulator of ME (Laugerette et al. 2012). Very recently, Mani et al. (2013) demonstrated that LPS concentration was increased by a meal rich in saturated fatty acids (SFA), while decreased after a meal rich in n-3 polyunsaturated fatty acids (n-3 PUFA).
  • this effect seems to be due to the fact that some SFA (e.g., lauric and mystiric acids) are part of the lipid-A component of LPS and also to n-3 PUFA's role on reducing LPS potency when substituting SFA in lipid-A
  • these experimental results suggest a pivotal role of CD14-mediated TLR4 activation in the development of LPS-mediated nutritional changes.
  • This suggests a link between gut microbiota, western diet, and obesity and indicates that gut microbiota manipulation can beneficially affect the host's weight and adiposity.
  • endotoxemia was independently associated with energy intake but not fat intake in a multivariate analysis
  • in vitro that endotoxemia activates pro-inflammatory cytokine/chemokine production via NFκB and MAPK signaling in preadipocytes and decreased peroxisome proliferator-activated receptor γ activity and insulin responsiveness in adipocytes.
  • T2DM patients have mean values of LPS that are 76% higher than healthy controls
  • LPS-induced release of glucagon, GH and cortisol, which inhibit glucose uptake, both peripheral and hepatic
  • LPSs also seem to induce ROS-mediated apoptosis in pancreatic cells
  • Recent evidence has been linking ME with dyslipidemia, increased intrahepatic triglycerides, development, and progression of alcoholic and nonalcoholic fatty liver disease
  • The hepatocytes, rather than hepatic macrophages, are the cells responsible for its clearance, being ultimately excreted in bile
  • All the subclasses of plasma lipoproteins can bind and neutralize the toxic effects of LPS, both in vitro (Eichbaum et al. 1991) and in vivo (Harris et al. 1990), and this phenomenon seems to be dependent on the number of phospholipids in the lipoprotein surface (Levels et al. 2001). LDL seems to be involved in LPS clearance, but this antiatherogenic effect is outweighed by its proatherogenic features
  • LPS produces hypertriglyceridemia by several mechanisms, depending on LPS concentration. In animal models, low-dose LPS increases hepatic lipoprotein (such as VLDL) synthesis, whereas high-dose LPS decreases lipoprotein catabolism
  • When a dose of LPS similar to that observed in ME was infused in humans, a 2.5-fold increase in endothelial lipase was observed, with consequent reduction in total and HDL. This mechanism may explain low HDL levels in ‘ME’ and other inflammatory conditions such as obesity and metabolic syndrome
  • It is known that the high-fat diet and the ‘ME’ increase intrahepatic triglyceride accumulation, thus synergistically contributing to the development and progression of alcoholic and NAFLD, from the initial stages characterized by intrahepatic triglyceride accumulation up to chronic inflammation (nonalcoholic steatohepatitis), fibrosis, and cirrhosis
  • On the other hand, LPS activates Kupffer cells leading to an increased production of ROS and pro-inflammatory cytokines like TNFα
  • high-fat diet mice presented with ME, which positively and significantly correlated with plasminogen activator inhibitor (PAI-1), IL1, TNFα, STAMP2, NADPHox, MCP-1, and F4/80 (a specific marker of mature macrophages) mRNAs
  • prebiotic administration reduces intestinal permeability to LPS in obese mice and is associated with decreased systemic inflammation when compared with controls
  • Cani et al. also found that high-fat diet mice presented with not only ME but also higher levels of inflammatory markers, oxidative stress, and macrophage infiltration markers
  • This suggests that important links between gut microbiota, ME, inflammation, and oxidative stress are implicated in a high-fat diet situation
  • high-fat feeding is associated with adipose tissue macrophage infiltration (F4/80-positive cells) and increased levels of chemokine MCP-1, suggesting a strong link between ME, proinflammatory status, oxidative stress, and, lately, increased CV risk
  • LPS has been shown to promote atherosclerosis
  • markers of systemic inflammation such as circulating bacterial endotoxin were elevated in patients with chronic infections and were strong predictors of increased atherosclerotic risk
  • As a TLR4 ligand, LPS has been suggested to induce atherosclerosis development and progression, via a TLR4-mediated inflammatory state.
  • Nathan Goodyear on 04 Aug 14
     
    Very nice updated review on Metabolic endotoxemia
Nathan Goodyear

Effect of Testosterone Administration on Liver Fat in Older Men With Mobility Limitatio... - 0 views

biomedgerontology.oxfordjournals.org/...gerona.gls259.abstract

testosterone low T low testosterone non-alcoholic fatty liver nonalcoholic steatohepatitis

shared by Nathan Goodyear on 02 Apr 13 - No Cached
  • Nathan Goodyear on 02 Apr 13
     
    Testosterone replacement in older men with low T not shown to improve liver fat content.  This has obvious implications to non-alcoholic hepatic steatosis.
Nathan Goodyear

Plasma Adiponectin in Nonalcoholic Fatty Liver Is Related to Hepatic Insulin Resistance... - 0 views

jcem.endojournals.org/...3498.short

NAFLD non-alcoholic fatty liver fatty liver insulin resistance fat IR obesity weight-loss

shared by Nathan Goodyear on 09 Jan 12 - No Cached
  • Nathan Goodyear on 09 Jan 12
     
    in those with nonalcoholic fatty liver disease, low adiponectin is associated with the insulin resistance, not the NAFLD.  But of course, insulin resistance leads to NAFLD
Nathan Goodyear

Probiotic as a Novel Treatment Strategy Against Liver Disease - Hepatitis Monthly - - K... - 0 views

hepatmon.com/?page=article&article_id=7521

probiotics liver disease cirrhosis hepatitis NAFLD non-alcoholic fatty liver

shared by Nathan Goodyear on 10 Feb 14 - No Cached
  • Nathan Goodyear on 10 Feb 14
     
    probiotics shown to be useful and safe in those with liver disease.
Nathan Goodyear

CLINICAL CHARACTERISTICS AND ENDOSCOPIC FINDINGS ASSOCIATED WITH BLASTOCYSTIS HOMINIS I... - 1 views

www.ajtmh.org/...213.long

blastocystis hominis blastocystis hepatitis

shared by Nathan Goodyear on 06 Apr 15 - No Cached
  • patients with alcoholic cirrhosis and chronic hepatitis experienced more severe symptoms when infected with B. hominis
  • individuals with chronic HBV infection were at increased risk of acquiring B. hominis
  • Among the 34 individuals with chronic HBV infection in this study, individuals who harbored B. hominis were more likely to have an abnormal liver function test result than those who did no
  • ...1 more annotation...
  • intense inflammatory cell infiltration, edematous lamina propria, and mucosal sloughing. However, the pathogenicity of B. hominis in human intestine has only been elucidated from case reports and a case series study
  • Nathan Goodyear on 06 Apr 15
     
    Blastocystis hominis.
Nathan Goodyear

The Mediterranean diet improves hepatic steatosis and insulin sensitivity in individual... - 0 views

www.sciencedirect.com/...S0168827813001347

NAFLD nutrition non-alcoholic fatty liver mediterranean diet liver disease fatty liver

shared by Nathan Goodyear on 27 Apr 16 - No Cached
  • Nathan Goodyear on 27 Apr 16
     
    Mediterranean diet reduced insulin resistance and liver steatosis in those with NAFLD.
Nathan Goodyear

Hypothalamic-Pituitary-Testicular Axis Disruptions in Older Men Are Differentially Link... - 0 views

press.endocrine.org/...jc.2007-1972

low T low Testosterone low T Testosterone aging LH hormone hormones men male SHBG

shared by Nathan Goodyear on 03 Sep 14 - No Cached
  • 0.4–2% annual decline
  • the age trend in free T was more substantial (−1.3% per annum)
  • The core hormonal pattern with increasing age is suggestive of incipient primary testicular dysfunction with maintained total T and progressively blunted free T associated with higher LH.
  • ...16 more annotations...
  • Obesity was associated with progressively lower total and free T independent of the simultaneous decrease in SHBG.
  • our data highlight the fact that LH was unchanged or even lower in older men in the face of lower T in obesity, suggesting that there may be a failure at the hypothalamic-pituitary level.
  • a change in BMI from nonobese to obese may be equivalent to a 15 yr fall in T.
  • This pattern supports the hypothesis that different underlying mechanisms influence the functions of the HPT axis: age predominantly affects testicular function, whereas obesity impairs hypothalamic/pituitary function.
  • the effects of aging on testicular function can be moderated by increased LH compensation for many decades
  • obesity impairs hypothalamic/pituitary function independent of age, arguably an adaptive response for which there should be no compensatory mechanism.
  • the concurrent but opposite (and separate) effects of obesity and age on SHBG
  • SHBG was negatively associated with increasing strata of obesity
  • Obesity is associated with insulin resistance (28), and the increased circulating insulin inhibits hepatic SHBG synthesis
  • the SHBG increase with age may be related to relative IGF-I deficiency (27), although this has not been directly proven.
  • Obesity is associated with peripheral and central insulin resistance (30) and proinflammatory cytokine production (TNFα and IL-6) from adipocytes (31) and central nervous system endocannibinoid release (32), all of which are potential candidates for abrogating hypothalamic endocrine and downstream reproductive axis functions.
    • Nathan Goodyear
      Nathan Goodyear on 03 Sep 14
       
      The HPA axis effect may be the result of inflammation.
  • The relationship between obesity and T can be bidirectional: low T may be the cause rather than consequence of obesity
  • chronic alcohol abuse is known to suppress LH (40), our data showed no significant association among the three hormones or SHBG and alcohol intake.
  • increase in total T in smokers occurs through a primary increase in SHBG with a compensatory rise in LH
  • the effects of obesity (BMI or waist circumference) was by far the most important determinant of variance in total T, whereas age per se was important for SHBG, LH, and free T with comorbidity and smoking being comparatively minor contributors
  • It is noteworthy that these predisposing lifestyle and health factors are modifiable. This implies that the apparent age-related decline in T may constitute a barometer of health and thus be potentially preventable and/or reversible.
  • Nathan Goodyear on 03 Sep 14
     
    Age induced decline in Testosterone is more associated with a decline in leydig cell function and thus elevated LH will be associated.  In contrast, obesity is more of a HPA axis disruption and thus LH may be normal to low.  The pulse amplitude is decrease.  No change in pulse frequency is noted.   With obesity, a decline in TT and fT was independent of SHBG. Aging is associated with a greater decrease in fT versus TT.
Nathan Goodyear

Polycystic Ovary Syndrome with Hyperandrogenism Is Characterized by an Increased Risk o... - 0 views

jcem.endojournals.org/...jc.2012-1382.abstract

PCOS NAFLD obesity insulin resistance polycystic ovarian syndrome ovary syndrome non-alcoholic fatty liver

shared by Nathan Goodyear on 30 Jul 12 - No Cached
  • Nathan Goodyear on 30 Jul 12
     
    PCOS with associated hyperandrogenism, is associated with increased risk of NAFLD versus PCOS without hyperandrogenism.
Nathan Goodyear

Resveratrol up-regulates hepatic uncoupling protein... [Nutr Res. 2012] - PubMed - NCBI - 0 views

www.ncbi.nlm.nih.gov/...23084643

resveratrol inflammation NAFLD non-alcoholic fatty liver high fat diet fat diet

shared by Nathan Goodyear on 23 Jul 13 - No Cached
  • Nathan Goodyear on 23 Jul 13
     
    Not only does resveratrol reduce inflammation, but resveratrol inhibits NAFLD in rats fed a high fat diet.  
Nathan Goodyear

Uric acid induces hepatic steatosis by generatio... [J Biol Chem. 2012] - PubMed - NCBI - 0 views

www.ncbi.nlm.nih.gov/...23035112

uric acid mitochondria non-alcoholic fatty liver fructose triglyceride oxidative stress fatty liver liver ATP

shared by Nathan Goodyear on 01 Oct 13 - No Cached
  • Nathan Goodyear on 01 Oct 13
     
    Elevated uric acid levels up regulate fructose metabolism to triglycerides and fatty liver.  This study finds that liver mitochondrial oxidative stress is also evident.  This mitochondrial dysfunction also leads to compromised ATP production and fat accumulation specifically through inhibition of aconitase..
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