Intrahepatic vascular changes in non-alcoholic fatty liver disease: Potential role of insulin-resistance and endothelial dysfunction

Abstract

Metabolic syndrome is a cluster of several clinical conditions characterized by insulin-resistance and high cardiovascular risk. Non-alcoholic fatty liver disease is the liver expression of the metabolic syndrome, and insulin resistance can be a frequent comorbidity in several chronic liver diseases, in particular hepatitis C virus infection and/or cirrhosis. Several studies have demonstrated that insulin action is not only relevant for glucose control, but also for vascular homeostasis. Insulin regulates nitric oxide production, which mediates to a large degree the vasodilating, anti-inflammatory and antithrombotic properties of a healthy endothelium, guaranteeing organ perfusion. The effects of insulin on the liver microvasculature and the effects of IR on sinusoidal endothelial cells have been studied in animal models of non-alcoholic fatty liver disease. The hypotheses derived from these studies and the potential translation of these results into humans are critically discussed in this review.

Keywords: Endothelial dysfunction; Insulin resistance; Metabolic syndrome; Non-alcoholic fatty liver disease.

Figure 1

The binding of insulin to its receptor activates a series of phosphorylations of downstream receptors that finally activate nitric oxide-production by endothelial nitric oxide synthase. A: The release of nitric oxide (NO) causes endothelium dependent vasodilation; B: Insulin-resistance causes the reduction of Insulin-induced activation of endothelial nitric oxide synthase (eNOS). This is associated with reduction of NO bioavailability and, finally, endothelial dysfunction.

Figure 2

Livers are isolated and perfused at a constant velocity. Any change of pressure will be directly proportional to the resistance offered by sinusoids to the flow of a buffer solution according to Ohm’s low applied to fluid-dynamic (ΔP = flow X resistance). This allows measuring the intrahepatic resistance offered by sinusoids.

Figure 3

The vascular-hypothesis of liver damage in non-alcoholic fatty liver disease considers sinusoidal endothelial dysfunction due to insulin-resistance a key factor for the initiation and perpetuation of liver damage from simple steatosis to steatohepatitis. Any strategy of treatment ameliorating insulin-resistance may be efficacious in ameliorating sinusoidal endothelial dysfunction. Drugs marked with ^a are those with a proven efficacy on liver microcirculation (Ref. [16,42,95,103,104]). (Histological images are courtesy of Dr. Marco Maggioni, IRCCS Ca’ Granda, Ospedale Maggiore Policlinico, Milan, Italy). NAFLD: Non-alcoholic fatty liver disease; NASH: Non-alcoholic steatohepatitis.