Pathogenesis of alcoholic liver disease: the role of nuclear receptors

Abstract

Ethanol consumption causes fatty liver, which can lead to inflammation, fibrosis, cirrhosis and even liver cancer. The molecular mechanisms by which ethanol exerts its damaging effects are extensively studied, but not fully understood. It is now evident that nuclear receptors (NRs), including retinoid x receptor alpha and peroxisome proliferator-activated receptors, play key roles in the regulation of lipid homeostasis and inflammation during the pathogenesis of alcoholic liver disease (ALD). Given their pivotal roles in physiological processes, NRs represent potential therapeutic targets for the treatment and prevention of numerous metabolic and lipid-related diseases including ALD. This review summarizes the factors that contribute to ALD and the molecular mechanisms of ALD with a focus on the role of NRs.

Figures

Figure 1

Hepatocyte RXRα modulates ethanol metabolism. ADH catalyzes the conversion of ethanol to acetaldehyde, a potent toxicant that accounts for most of the toxic effects of ethanol. Acetaldehyde produced from ethanol is further converted to the non-toxic acetate by a mitochondrial ALDH2. Both steps are coupled with the reduction of NAD+ to NADH. Both ethanol and acetaldehyde can be metabolized by CYP2E1. CYP2E1 has been implicated as the source of free radicals generated by ethanol metabolism. Hepatocyte RXRα deficiency results in a significant increase in hepatic ADH activity. In addition, mitochondrial ALDH2 and cytosolic ALDH activity is reduced when hepatocyte RXRα is not expressed. Accordingly, hepatic acetaldehyde clearance is reduced due to the lack of hepatocyte RXRα. Furthermore, SAMe and glutathione levels as well as the expression of GCLC, GST and GPx genes are significantly reduced due to the lack of hepatocyte RXRα. ADH, alcohol dehydrogenase; ALDH, aldehyde dehydrogenase; CYP2E1, cytochrome P450 2E1; GST, glutathione S transferase; GCLC, glutamate–cysteine ligase catalytic subunit; GPx-1, glutathione peroxidase 1; GNMT, glycine N-methyl transferase; MAT, methionine adenosyl transferase; AHCY, adenosylhomocysteinase; SAMe, S-adenosylmethionine; SAH, S-adenosylhomocysteine

Figure 2

Interaction among nuclear receptors (NRs), alcohol and lipid homeostasis. Research on the role of nuclear receptors in ALD have focused mainly on PPARs. The hepatic RXRα levels are decreased by alcohol administration., Down-regulation of PPARα expression and fatty liver are observed following ethanol administration., The activation of SREBP-1c by ethanol feeding is associated with increased expression of lipogenic genes as well as the accumulation of triglycerides. The activation of SREBP-1c has been suggested to involve LXR. FXR represses lipogenesis by interfering with the expression of SREBP-1c through SHP, which inhibits the activity of LXR. Ethanol increases the mRNA levels of PPARγ isoforms and the expression level of down-stream target fatty-acid translocase (CD36). Fatty acids can induce CAR expression. The activation of CAR suppresses lipogenesis by decreasing the active form of SREBP-1c. PPARγ, CD36, SCD-1 and FAE are direct transcriptional targets of PXR. HNF4α is central regulator of bile acid and lipid homeostasis genes. These complex interactions among NRs involved in lipid homeostasis determine fat accumulation in the liver. SREBP-1c, sterol regulatory element-binding protein-1c; PPARα, peroxisome proliferator-activated receptors α; CPT-1, carnitine palmitoyl transferase-1; ACC, acetyl-CoA carboxylase; FAS, fatty acid synthase; SCD, stearoyl CoA desaturase; FAE, fatty acid elongase; FXR, farnesoid x receptor, LXR, liver x receptor, PXR, pregnane x receptor; CAR, constitutive androstane receptor; RXR, retinoic x receptor; HNF4α, hepatocyte nuclear factor 4α