Mitochondrial dysfunction in nonalcoholic fatty liver disease and alcohol related liver disease

Abstract

Fatty liver disease constitutes a spectrum of liver diseases which begin with simple steatosis and may progress to advance stages of steatohepatitis, cirrhosis, and hepatocellular carcinoma (HCC). The two main etiologies are-alcohol related fatty liver disease (ALD) and nonalcoholic fatty liver disease (NAFLD). NAFLD is a global health epidemic strongly associated with modern dietary habits and life-style. It is the second most common cause of chronic liver disease in the US after chronic hepatitis C virus (HCV) infection. Approximately 100 million people are affected with this condition in the US alone. Excessive intakes of calories, saturated fat and refined carbohydrates, and sedentary life style have led to explosion of this health epidemic in developing nations as well. ALD is the third most common cause of chronic liver disease in the US. Even though the predominant trigger for onset of steatosis is different in these two conditions, they share common themes in progression from steatosis to the advance stages. Oxidative stress (OS) is considered a very significant contributor to hepatocyte injury in these conditions. Mitochondrial dysfunction contributes to this OS. Role of mitochondrial dysfunction in pathogenesis of fatty liver diseases is emerging but far from completely understood. A better understanding is essential for more effective preventive and therapeutic interventions. Here, we discuss the pathogenesis and therapeutic approaches of NAFLD and ALD from a mitochondrial perspective.

Keywords: Mitochondria; metabolic syndrome; mitochondrial dysfunction; nonalcoholic fatty liver disease (NAFLD); nonalcoholic steatohepatitis (NASH).

Figure 1

Diagrammatic representation of the role of mitochondria in energy metabolism inside cell. Energy stored in food constituents are captured by NAD and FAD. The high energy electrons are then transferred to ETC where it gradually moves from high energy state to low energy state. The energy released in this process is harnessed to propel protons across the IMM creating a proton gradient across the IMM. Protons then diffuse along its concentration gradient at V. The energy released in this process is harnessed to generated ATP from ADP. I, Complex I; II, Complex II; III, Complex III, IV, Complex IV; V, Complex V; CoQ, Coenzyme Q; ETC, electron transport chain; FAD, flavin adenine dinucleotide; IMM, inner mitochondrial membrane; NAD, nicotinamide adenine dinucleotide; OMM, outer mitochondrial membrane; TCA, tricarboxylic acid.

Figure 2

Origins of hepatic fat in nonalcoholic fatty liver disease.

Figure 3

Primary pathway for alcohol metabolism in the hepatocytes. ADH, alcohol dehydrogenase; ALDH2, aldehyde dehydrogenase 2.

Figure 4

Schematic representation of the role of mitochondria in pathogenesis of NAFLD. There is excessive electron leak from the electron transport chain in NAFLD leading to excessive ROS and oxidative stress. The ROS activates inflammatory pathways via NF- κB and NLRP3 pathways. The inflammatory cytokines activate Kuppfer cells in sinusoids. Mitochondrial oxidative stress also leads to MPTP formation and release of mtDNA in cytoplasm and activation of apoptosis/necrosis machinery. mtDNA activates NLRP3 inflammasome leading to maturation of the cytokine, IL-1β. mtDNA released after hepatocyte necrosis activates TLR9 on Kuppfer cells. Activated Kuppfer cells produce inflammatory cytokines and activate HSC. HSC are fibrogenic. Persistent HSC activation leads to hepatic fibrosis. The inflammatory cytokines released from hepatocytes, and innate immune cells lead to hepatic inflammation, perpetuation of oxidative stress and hepatocyte necroptosis. Loss of hepatocytes, progressive fibrosis, and regenerating nodules from progenitor cell proliferation results in cirrhosis. Uncontrolled proliferation of progenitor cells predisposes to hepatocellular carcinoma. NAFLD, nonalcoholic fatty liver disease; IL, interleukin; HSC, hepatic stellate cells; mtDNA, mitochondrial DNA; NF-κB, nuclear factor-Κb; NLRP3, nucleotide-binding oligomerization domain-like receptor family, pyrin domain-containing 3; ROS, reactive oxygen species; TGF-β, transforming growth factor-β; TNF-α, tumor necrosis factor-α.