Molecular mediators of hepatic steatosis and liver injury

Abstract

Obesity and its associated comorbidities are among the most prevalent and challenging conditions confronting the medical profession in the 21st century. A major metabolic consequence of obesity is insulin resistance, which is strongly associated with the deposition of triglycerides in the liver. Hepatic steatosis can either be a benign, noninflammatory condition that appears to have no adverse sequelae or can be associated with steatohepatitis: a condition that can result in end-stage liver disease, accounting for up to 14% of liver transplants in the US. Here we highlight recent advances in our understanding of the molecular events contributing to hepatic steatosis and nonalcoholic steatohepatitis.

Figure 1

Metabolic alterations resulting in hepatic triglyceride accumulation in insulin-resistant states. Insulin resistance is manifested by hyperinsulinemia, increased hepatic glucose production, and decreased glucose disposal. In adipocytes, insulin resistance increases hormone-sensitive lipase (HSL) activity, resulting in elevated rates of triglyceride lipolysis and enhanced FFA flux to the liver. FFAs can either be oxidized in the mitochondria to form ATP or esterified to produce triglycerides for storage or incorporation into VLDL particles. In liver, hyperinsulinemia induces SREBP-1c expression, leading to the transcriptional activation of all lipogenic genes. Simultaneously, hyperglycemia activates ChREBP, which transcriptionally activates L-PK and all lipogenic genes. The synergistic actions of SREBP-1c and ChREBP coordinately activate the enzymatic machinery necessary for the conversion of excess glucose to fatty acids. A consequence of increased fatty acid synthesis is increased production of malonyl-CoA, which inhibits CPT-1, the protein responsible for fatty acid transport into the mitochondria. Thus, in the setting of insulin resistance, FFAs entering the liver from the periphery, as well as those derived from de novo lipogenesis, will be preferentially esterified to triglycerides. ACL, ATP citrate lyase; CPT-1, carnitine palmitoyl transferase-1; FAS, fatty acid synthase; LCE, long-chain fatty acyl elongase.

Figure 2

Consequences of hepatic AMPK activation. The pharmacologic agents, metformin and thiazolidinediones (TZDs), activate AMPK in the liver. In addition, the deletion of SCD results in AMPK activation through an undetermined mechanism. The activation of AMPK reduces lipogenesis through three independent mechanisms. Activated AMPK phosphorylates and inhibits the activity of ACC, which reduces malonyl-CoA formation. ChREBP is phosphorylated by activated AMPK, which inhibits its entry into the nucleus, thus suppressing L-PK and lipogenic gene expression. SREBP-1c expression is reduced by activated AMPK through undefined mechanisms. The cumulative result of AMPK activation, whether by drugs or through the deletion of SCD, is a reduction in fatty acid synthesis, decreased malonyl-CoA concentrations, and increased CPT-1 activity, resulting in increased fatty acid oxidation.

Figure 3

Mechanisms of lipid-induced cellular injury in NAFLD. ROS are formed through oxidative processes within the cell. In the mitochondria, impaired MRC activity leads to the formation of superoxide anions and hydrogen peroxide. The accumulation of fatty acids in the cytosol increases fatty acid oxidation in peroxisomes and the ER. The initial reaction in peroxisomal β oxidation is catalyzed by acyl-CoA oxidase (AOX) that forms hydrogen peroxide through the donation of electrons to molecular oxygen. Microsomal w oxidation is catalyzed by cytochrome P450 (CYP) enzymes 2E1, 4A10, and 4A14, which form ROS through flavoprotein-mediated donation of electrons to molecular oxygen. PUFAs are extremely susceptible to lipid peroxidation by ROS. By-products of PUFA peroxidation are aldehydes, such as HNE and MDA. These aldehydes are themselves cytotoxic and can freely diffuse into the extracellular space to affect distant cells. ROS and aldehydes induce oxidative stress and cell death via ATP and NAD depletion, DNA and protein damage, and glutathione depletion. Additionally, they induce inflammation through the production of proinflammatory cytokines, leading to neutrophil chemotaxis. Within the extracellular space, HNE and MDA are themselves potent chemoattractants for neutrophils. Finally, ROS and products of lipid peroxidation can lead to fibrosis by activating hepatic stellate cells, which synthesize collagen and perpetuate the inflammatory response.