Insulin, glucose and FFA, whose serum concentrations are increased as a result
of insulin resistance, represent both biochemical precursors and metabolic
signals with steatogenic valence. Hyperinsulinemia and hyperglycemia activate
hepatic transcription factors, such as SREBP-lc (Sterna Regulator
Element-Binding Protein and ChREBP (Carbohydrate Response Element Binding
Protein), which activate enzymes for the conversion of excess glucose into fatty
acids. Transcription activated during insulin-resistance is the Peroxisome
Proliferator-Activated Receptor y (PPARy), implicated in the differentiation of
adipocytes and in the accumulation of triglycerides in the liver resulting in
steatosis.
The steatosis itself, once emerged as a phenotypic event, promotes the synthesis and secretion of TNFa by the increased intrahepatic FFA concentration. TNFa interferes with the signalling of insulin at the receptor level, inducing "steatosis-associated" (hepatic) insulin-resistance, a biochemical event that associates with the "peripheral" insulin resistance of obesity. The result is a further intrahepatic accumulation of fat.
A particularly interesting physiopathological field is that of the relationship between hepatitis C virus and insulin resistance. A recent study showed that patients with mild-to-moderate chronic hepatitis C have significant insulin resistance compared to healthy controls of the same age, BMI and physical activity and that this insulin resistance is mainly peripheral with a minimal contribution from the liver, contrary to what has been reported so far.
The steatosic liver is sensitized to further damage. In this phase the FFA
derived from adipocyte lipolysis induces a series of pro-inflammatory events:
• production of oxygen free radicals (ROS), due to their oxidation (peroxidation),
with consequent mitochondrial damage, damage to the respiratory chain, reduced
availability of adenosine triphosphate, synthesis of mediators of inflammation
including TNFa, TGFp, IL6, Fas ligand and depletion of the normal antioxidant
systems present in the liver;
• direct activation of the IKKβ / NF-kB pathway (the nuclear factor kB and its
activator I kappa B kinase beta) in hepatocytes, through a lysosomal mechanism
dependent on cathepsin B, with the translocation of Bax to the lysosomes, their
subsequent destabilization and release of cathepsin B in the cytosol.
This induces NF-kB activation, through IKKB and subsequent increase of TNFa
expression and increased transcription of a wide range of inflammatory mediators,
including TNFa, IL6 and IL1, as well as activation of Kupffer cells. Furthermore,
increased circulating leptin levels and reduced adiponectin levels in the obese
subject may contribute to the progression of steatosis to NASH. Leptin
stimulates the release by the hepatocytes of osteopontin, a proinflammatory
cytokine. On the other hand, the production of adiponectin, an anti-inflammatory
adipokine, can be suppressed by TNFa released by the adipose tissue macrophages.
Hyperinsulinemia and hyperglycemia during insulin resistance can stimulate the
synthesis of the Connective Tissue Growth Factor (CTGF) in hepatic stellate
cells with consequent transformation from the quiescent state to the activated
myofibroblastic phenotype, protein deposition from the extracellular matrix and
development of liver fibrosis. Hepatic stellate cells can then be stimulated
directly by both leptin and mediators such as osteopontin, angiotensin II and
norepinephrine.