The Interplay between Insulin Resistance, Inflammation, Oxidative Stress, Base Excision Repair and Metabolic Syndrome in Nonalcoholic Fatty Liver Disease

Abstract

One of the most common chronic liver disorders, affecting mainly people in Western countries, is nonalcoholic fatty liver disease (NAFLD). Unfortunately, its pathophysiological mechanism is not fully understood, and no dedicated treatment is available. Simple steatosis can lead to nonalcoholic steatohepatitis and even to fibrosis, cancer, and cirrhosis of the liver. NAFLD very often occurs in parallel with type 2 diabetes mellitus and in obese people. Furthermore, it is much more likely to develop in patients with metabolic syndrome (MS), whose criteria include abdominal obesity, elevated blood triacylglycerol level, reduced high-density lipoprotein cholesterol level, increased blood pressure, and high fasting glucose. An important phenomenon in MS is also insulin resistance (IR), which is very common in NAFLD. Liver IR and NAFLD development are linked through an interaction between the accumulation of free fatty acids, hepatic inflammation, and increased oxidative stress. The liver is particularly exposed to elevated levels of reactive oxygen species due to a large number of mitochondria in hepatocytes. In these organelles, the main DNA repair pathway is base excision repair (BER). The present article will illustrate how impairment of BER may be related to the development of NAFLD.

Keywords: DNA repair; base excision repair; inflammation; insulin resistance; metabolic syndrome; nonalcoholic fatty liver disease; oxidative stress.

Figure 1

The development of fatty liver beginning with the accumulation of fats in primarily healthy hepatocytes. Prolonged inflammation in the fatty liver leads to steatosis and fibrosis of tissue. The following scaring of the liver triggers irreversible damage, and cirrhosis occurs.

Figure 2

The insulin signaling: A: normal insulin level; B: increased insulin level. Abbreviations: Akt: protein kinase B; IRS1: insulin receptor substrate 1; PI3K: phosphoinositide 3-kinase; PIP2: phosphatidylinositol biphosphate; ROS: reactive oxygen species.

Figure 3

Scheme presenting the relationship between BER and insulin signaling. Abbreviations: GDP: guanosine diphosphate; GTP: guanosine triphosphate; OGG1: oxoguanine glycosylase; PI3K: phosphoinositide 3-kinase; RNA pol II: RNA polymerase II; ROS; reactive oxygen species.