Non-alcoholic Fatty Liver Disease Figure 2: Pathogenesis of Non-alcoholic Fatty Liver Disease Genetic factors
Defect in insulin signaling
Peripheral IR Environmental factors
Lipolysis Increase FFA TNF-α NF-κΒ
↑ FFA oxidation steatosis
Hepatic IR
De novo lipogenesis ER stress
↑ Lipid synthesis
↑ Apoptosis
↑ JNK
ROS Via ↑ leptin ↓ Adiponectin
Activate HSC Fibrosis
Adipose tissue Macrophage activation
Peripheral insulin resistance (IR) leads to increased delivery of free fatty acids (FFAs) to the liver, resulting in an inbalance between oxidation and export of FFA and uptake and synthesis, thus promoting hepatic steatosis. The production of reactive oxygen species (ROS) from the FFA metabolism via oxidation causes apoptosis and triggers inflammatory injury and activation of hepatic stellate cell (HSC) leading to liver fibrosis. Increased hepatic FFA also results in endoplasmic reticulum (ER) stress and hepatocyte inflammation and apoptosis via activation of c-Jun N-terminal kinase (JNK). Adipose tissue secretes adipocytokines such as leptin that has a direct role in the regulation of adipocyte metabolism and in several insulin-mediated processes. Adiponectin is anti-inflammatory and antisteatotic. Its secretion is partly regulation by tumour necrosis factor-alpha (TNF-α), synthesis of which is promoted by nuclear factor kappa B (NF-κB). Source: Cheung and Sanyal, 2009.63
low-grade inflammation by producing pro-inflammatory cytokines such as tumour necrosis factor-α (TNF-α) and interleukin-6 (IL-6).56
The
liver is assumed to be the major source of CRP production. It has, however, been suggested that adipose tissue can also be a direct source of CRP. In severely obese patients with a large amount of body fat, adipose tissue might well significantly contribute to the increased circulating CRP levels.57–59
development and progression of cardiovascular disease.42
This chronic inflammation plays a role in the Excess
visceral adiposity is probably the missing link between inflammation, cardiovascular disease and type 2 diabetes.60
Because visceral adiposity seems to be an important indicator for metabolic and cardiovascular alterations, it has also been linked to metabolic syndrome, a complex condition characterised by insulin resistance, dyslipidaemia and hypertension.15
In 2005, the
International Diabetes Federation even suggested adjusting the definition of metabolic syndrome by including central obesity (measured by waist circumference) as an essential criterion.61
The
clinical evidence for the definition of the syndrome and the underlying pathogenesis, however, is the topic of many discussions.
Role of Visceral Fat in the Pathogenesis of Non-alcoholic Fatty Liver Disease and Non-alcoholic Steatohepatitis
For a recent review on the pathogenesis of NAFLD/NASH, we refer to the work of Fabbrini et al.62
and to Figure 2.63 In 1998, the ‘two hit’
model of the pathogenesis of NAFLD was proposed. The ‘first hit’ is the excessive accumulation of fat in the liver. This is a consequence of an imbalance between the influx and synthesis of liver lipids on the one hand and their β-oxidation and export on the other hand.
98
The fatty liver becomes sensitive to presumed ‘second hits’ leading to hepatocyte injury, inflammation and fibrosis. These second hits can be oxidative stress (and subsequent lipid peroxidation) and cytokines such as TNF-α, interleukin-8 (IL-8) and transforming growth factor-β (TGF-β).64,65
Emerging data question this ‘simple’ model and suggest that the pathogenesis of NAFLD and NASH is probably much more complex and not yet completely understood.66
The distribution of body fat may be at least as important as total adipose tissue in the development of hepatic steatosis. Central adiposity has been shown to be associated with NAFLD in normal weight, obese and diabetic individuals.13
Van der Poorten et al.67
demonstrated that visceral fat correlates with inflammation and fibrosis in human NAFLD. Patients with NASH have visceral obesity in 48 % of cases versus 31 % of patients with pure steatosis (p=0.005).68 According to Eguchi et al.,69
the severity of fatty liver, evaluated by
ultrasonography and CT, was positively correlated with visceral fat accumulation (evaluated by abdominal CT) and insulin resistance in both obese and non-obese subjects, suggesting that hepatic fatty infiltration in NAFLD may be influenced by visceral fat accumulation regardless of body mass index (BMI). A strong association was found between visceral fat accumulation and liver steatosis in morbidly obese women.70
Park et al.71 found that visceral abdominal adiposity
(measured by CT) is an independent risk factor for hepatic steatosis in healthy living (disease-free population) liver donors. They concluded that VAT is more important than BMI or obesity itself for hepatic steatosis in men and women. We recently demonstrated a correlation between VAT (measured by CT) and liver tests in an obese population.72
Visceral adiposity has also been shown, together with insulin resistance, to be an independent predictor of the presence of
EUROPEAN ENDOCRINOLOGY
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