The Role of Visceral Adipose Tissue in the Pathogenesis of Non-alcoholic Fatty Liver Disease
a steatosis-associated increase in portal pressure.73 is also an important risk factor for paediatric NAFLD.74
Visceral adiposity Based on all
these data, visceral adiposity is currently considered to be a major contributor to fatty liver, especially in the insulin-resistant state. Some evidence even suggests that visceral adiposity is more influential than body mass in terms of predicting the presence of fatty liver.75
The mechanisms linking VAT and the liver are currently poorly understood. The drainage of the venous blood of the gastrointestinal system, including the VAT, via the portal system to the liver represents a unique anatomical link between the two. Via the portal vein, VAT can directly influence the liver. NAFLD-induced changes in liver haemodynamics might inversely influence VAT.76,77
FFA flux,
insulin resistance and adipokines are, along with inflammation and oxidative stress, currently considered to be the main factors in NAFLD pathogenesis related to VAT.
Free Fatty Acid Flux and Alterations in Lipid Metabolism
VAT has greater lipolytic potential than subcutaneous adipose tissue, and the release of FFA from visceral fat directly into the portal circulation creates a first-pass effect. Serum FFA derived from VAT by lipolysis are the main source of hepatic TG in NAFLD, although hepatic de novo lipogenesis and dietary fat supply contribute to the pathogenesis of NAFLD.78
Increased FFA concentrations, in turn, are
considered a major mediator of insulin resistance. In contrast, FFA flux and concentrations in individuals with predominantly lower body obesity tend to be normal, regardless of BMI. Therefore, patients with central obesity are typically insulin-resistant, and more commonly present with NAFLD than patients with lower-body obesity.12,79
It
appears, however, that visceral fat is a better predictor for insulin resistance and liver dysfunction than BMI.20
Excessive intrahepatic triglyceride (IHTG) content in obese subjects is associated with alterations in both adipose tissue and hepatic lipid metabolism: subjects with NAFLD have increased rates of adipose tissue TG lipolysis and hepatic very low-density lipoprotein (VLDL)-TG secretion. Fabbrine et al.80
showed that the increase in
VLDL-TG secretion was caused by an increased incorporation of non-systemic fatty acids, presumably from lipolysis of intrahepatic and intra-abdominal fat and de novo lipogenesis, into VLDL. These data hence suggest that increased IHTG content is not simply a marker of altered hepatic metabolic function, but that it is directly involved in the pathophysiology of NAFLD. Moreover, the increase in VLDL-TG secretion, which is the major source of circulating TG, is probably responsible for the increase in serum TG concentrations commonly observed in patients with NAFLD. The dissociation in VLDL- TG and VLDL-apolipoprotein B100 (apoB100) kinetics suggests that a failure to increase adequately the secretion rate of apoB100, which provides the framework for TG incorporation into VLDL, limits the liver’s capacity to export TG.
Insulin Resistance
Insulin resistance is thought to be inevitably linked with the pathogenesis of NAFLD.81
Obesity, type 2 diabetes and
hyperlipidaemia are associated with insulin resistance and are often present in patients with NAFLD. There are even insulin-resistant patients with NAFLD who are not obese and have a normal glucose tolerance.68
resistance in NAFLD, however, is the subject of debate. Is the initial resistance in the periphery (skeletal muscle and adipose tissue) or in the liver?82
Insulin has predominantly anabolic effects on glucose and fat metabolism by promoting glucose uptake, glycolysis and glycogen synthesis in skeletal muscle, by promoting triglyceride synthesis and storage (through inhibition of lipoprotein lipase) in adipose tissue and by inhibition of glycogenolysis and gluconeogenesis in the liver and release of glucose from the liver.83
Insulin resistance,
therefore, decreases glucose uptake and utilisation in muscle. In adipose tissue, lipolysis is not adequately suppressed by insulin, with subsequent release of glycerol and non-esterified fatty acids (NEFA) into the circulation. In the liver, insulin resistance is responsible for the overproduction of glucose despite fasting hyperinsulinaemia.18
The metabolic effect of peripheral insulin resistance, partially mediated by decreased plasma adiponectin levels, includes fatty acid flux from adipose tissue to the liver and induces the accumulation of fat in the liver. Elevated plasma glucose can further increase hepatic fat content through multiple pathways, resulting in an overproduction of VLDL-1 particles and leading to the characteristic dyslipidaemia associated with type 2 diabetes.84,85
Molecules such as TNF-α, fatty acids and
others appear to interfere with the insulin signalling pathway. The effects of insulin resistance in muscle and adipose tissue interact with the compensatory hyperinsulinaemia on tissues that remain insulin- sensitive. This causes changes in lipid metabolism, such as enhanced peripheral lipolysis, increased hepatic uptake of FFA, and increased hepatic triglyceride synthesis. The influx and neosynthesis of FFA are more important than FFA oxidation and triglyceride secretion, resulting in an accumulation of fat in the liver. Adipose tissue insulin resistance is even associated with increased liver fat content independently of obesity in humans.80,86,87
This hepatic fat subsequently contributes to an
impaired glucose metabolism and insulin sensitivity within the liver.3,11,18 Recent data indicate that hyperinsulinaemia is probably the consequence of, rather than a cause of, NAFLD.78
Adipocytokines
Adipocytokines are likely to be involved in the pathogenesis of NAFLD since they are secreted from both adipose tissue and the liver. For several adipocytokines, such as leptin, adiponectin, TNF-α, retinol-binding protein-4 (RBP4) or fetuin-A, a crucial role in the development and progression of fatty liver has been suggested. Dysregulation of adipocytokines may represent an important mechanism linking increased fat mass in obesity with the development of fatty liver disease.88,89
Cytokines are involved in the recruitment and
activation of Kupffer cells (resident hepatic macrophages) and are responsible for the transformation and perpetuation of hepatic stellate cells to the myofibroblastic phenotype.32,90
TNF-α and IL-6, two important pro-inflammatory cytokines, are known to be elevated in obesity and NAFLD. TNF-α, together with IL-6 and chemokines, mediates macrophage infiltration which causes inflammation of adipose tissue. This leads to insulin resistance and dysregulation of the secretion of adipokines.91–93
Hypoadiponectinaemia is considered to be involved in the aetiology of hepatic steatosis independently of VAT content, and is considered to be an important factor in the progression of fibrosis.94
Adiponectin
Insulin resistance classically involves multiple sites: muscle, adipose tissue and the liver. The primary site of insulin
EUROPEAN ENDOCRINOLOGY
may protect the liver from inflammation via direct antagonism of TNF-α.89
Adiponectin concentrations inversely correlate with fat mass and are downregulated in obesity and type 2 diabetes. Adiponectin
99
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