Role of Oxidative Stress in Hepatic and Extrahepatic Dysfunctions during Nonalcoholic Fatty Liver Disease (NAFLD)

Abstract

Nonalcoholic fatty liver disease (NAFLD) is a pathology that contains a broad liver dysfunctions spectrum. These alterations span from noninflammatory isolated steatosis until nonalcoholic steatohepatitis (NASH), a more aggressive form of the disease characterized by steatosis, inflammatory status, and varying liver degrees fibrosis. NAFLD is the most prevalent chronic liver disease worldwide. The causes of NAFLD are diverse and include genetic and environmental factors. The presence of NASH is strongly associated with cirrhosis development and hepatocellular carcinoma, two conditions that require liver transplantation. The liver alterations during NAFLD are well described. Interestingly, this pathological condition also affects other critical tissues and organs, such as skeletal muscle and even the cardiovascular, renal, and nervous systems. Oxidative stress (OS) is a harmful state present in several chronic diseases, such as NAFLD. The purpose of this review is to describe hepatic and extrahepatic dysfunctions in NAFLD. We will also review the influence of OS on the physiopathological events that affect the critical function of the liver and peripheral tissues.

Figure 1

Intrahepatic complications in nonalcoholic fatty liver disease (NAFLD). NAFLD's pathophysiology is affected by genetic and environmental factors such as diet, bisphenol A (BPA), leading to obesity and insulin resistance (IR). Adipose tissue gain contributes to chronic low-grade inflammation and increases free fatty acids (FFA) mobilization, resulting in visceral and ectopic fat deposition. In NAFLD, one of the main alterations is the hepatic steatosis. Thus, steatosis increases FFA, which increases intrahepatic triglycerides levels. This significant lipidic increase inside the liver results in lipotoxicity and oxidative stress (OS). OS and lipotoxicity induce mitochondrial dysfunction, hepatocyte apoptosis, and hepatic inflammation, increasing profibrotic factors that contribute to liver fibrosis. Besides, there is a failed attempt to regenerate the liver. Together, these tissue alterations contribute to hepatic dysfunction. Together, the impaired lipidic metabolism, the increase of proinflammatory cytokines, and the OS can induce hepatic dysfunction that favors NAFLD progression. Created with http://BioRender.com.

Figure 2

The effect of oxidative stress (OS) in hepatic tissue during nonalcoholic fatty liver disease (NAFLD). In NAFLD, significant lipidic increase inside the liver results in lipotoxicity, which induces oxidative stress (OS), with a marked reactive oxygen species (ROS) increase. OS is the main contributor to NAFLD development due to decreased antioxidant systems, mitochondrial dysfunction, and an increase in unfolded protein response (UPR) by endoplasmic reticulum (ER) stress. Furthermore, an OS increment is due to NAFLD's negative consequences as the iron increase and hypoxia. Lipotoxicity given by NAFLD can directly induce OS and induce organelle damage, as mitochondrial and ER dysfunction. Also, there is an impairment in β-oxidation due to a decrease in peroxisome proliferator-activated receptor alpha (PPARα) activity, which increases intrahepatic lipids levels, inducing hepatic inflammation. At the same time, the phospholipid oxidation in the mitochondrial membrane decreases electron transport chain (ETC) that increases electron leakage, diminishing adenosine triphosphate (ATP) production, and generating antioxidant systems dysfunction characterized by the decrease in nuclear factor-(erythroid-derived 2) (Nrf2) activity. Together, these mechanisms related to mitochondrial dysfunction increases OS. On the other hand, lipotoxicity induces an increase of UPR, causing ER dysfunction. The ER dysfunction increases Sarco/endoplasmic reticulum Ca²⁺-ATPase (SERCA) activity and intracellular Ca⁺² (Ca⁺²i) levels, leading to the opening of the mitochondrial permeability transition pore (mPTP), causing an increase in ROS production. The ROS increment causes a decrease in nitric oxide (NO) levels, causing a reduction in the liver's vasodilatation. Together, all these mechanisms increase ROS production, increasing OS in hepatic tissue, which causes inflammation, hepatocytes apoptosis, and fibrosis during NAFLD progression. Created with http://BioRender.com

Figure 3

Extrahepatic tissue complications by nonalcoholic fatty liver disease (NAFLD). In skeletal muscle, sarcopenia is induced by NAFLD. The development of sarcopenia is characterized by muscle weakness and fibrosis. Among the factors that contribute to sarcopenia in NAFLD are the increase of proinflammatory cytokines (tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6)), classical renin-angiotensin system (RAS), myostatin, and ammonium. In cardiac tissue, the main complication induced by NAFLD is cirrhotic cardiomyopathy (CCM). CCM is characterized by systolic and diastolic dysfunction in the ventricle and altered electromechanical patterns. Besides, NAFLD also induces impairment in vascular endothelium, characterized by hemodynamic changes, mainly caused by the increase of classical RAS and represented by the rise in volemia and portal hypertension. NAFLD can induce acute renal failure (ARF) and chronic kidney diseases (CKD) in the renal system. ARF is developed in NAFLD patients with hypovolemia caused by a vasoconstriction response, classical RAS activation, and also activation of the sympathetic nervous system (SNS). CKD is characterized by impaired filtration. This impairment increases creatinine serum levels and induces proteinuria. NAFLD is related to peripheral neuropathy (PN) and hepatic encephalopathy (HE) in the nervous system. PN related to NAFLD is a pathology characterized by altered myelin sheath in peripheral nerves with neuronal loss. The HE causes brain edema and atrophy and is favored by hyperammonemia (HA) in NAFLD. Created with http://BioRender.com

Figure 4

Harmful effects of oxidative stress (OS) in extrahepatic tissues due to nonalcoholic fatty liver disease (NAFLD). In skeletal muscle, NAFLD is responsible for the development of sarcopenia and fibrosis. NAFLD causes an increase of proinflammatory cytokines (tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6)), reactive oxygen species (ROS) production, classical renin-angiotensin system (RAS) activation, and hyperammonemia (HA), which stimulates an increment in myostatin levels. Together these factors are responsible for increased NADPH oxidase (NOX) activity and mitochondrial dysfunction, which produce ROS. Furthermore, ROS's increment increases the ubiquitin-proteasome system (UPS) and autophagy activity, favoring sarcopenia. Simultaneously, the increase in ROS stimulates higher production of collagen III and fibronectin, contributing to fibrosis in skeletal muscle. Concerning the cardiovascular system, the ROS increment by NAFLD causes impairment in cardiac and vascular functions. ROS is responsible for impaired ion flux, causing impaired contractility, ventricle hypertrophy, and cardiomyocytes apoptosis. ROS and the RAS activity at the vascular level cause portal hypertension and endothelial dysfunction (ED), characterized by endothelial inflammation and lipotoxicity in the tissue. The renal system suffers alterations in excretion due to glomerular and tubular damage by NAFLD. All these damages are caused mainly by vasoconstriction due to NAFLD, which causes hypoxia, inflammation, increasing NOX, xanthine oxidase (XO) activity, and reducing nuclear factor-(erythroid-derived 2) (Nrf2) levels, raising even more ROS levels. At the central nervous system, NAFLD causes hyperammonemia (HA), which provoked astrocyte swelling. Astrocyte swelling increases NOX and nNOS activity, causing an increase in ROS levels. The increment in ROS levels triggers protein tyrosine nitration, ribonucleic acid (RNA) oxidation, and Zn⁺² mobilization. On the other hand, NAFLD increases ROS levels in the bloodstream; this ROS causes progressive demyelination of peripheral nerves with eventual axonal loss. Created with http://BioRender.com