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.
Testosterone replacement in older men with low T not shown to improve liver fat content. This has obvious implications to non-alcoholic hepatic steatosis.
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
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
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
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.
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.
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.
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.
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..