J Clin Invest 114(2): 147-152

Molecular mediators of hepatic steatosis and liver injury

^{Departments of Internal Medicine and}^{Molecular Genetics, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas, USA.}

Address correspondence to: Jay D. Horton, Departments of Internal Medicine and Molecular Genetics, University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Boulevard, Room L5-238, Dallas, Texas 75390-9046, USA. Phone: (214) 648-9677; Fax: (214) 648-8804; E-mail: ude.nretsewhtuostu@notroh.yaj.

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.

Abstract

Nonalcoholic fatty liver disease (NAFLD) is a clinicopathological term that encompasses a disease spectrum ranging from simple triglyceride accumulation in hepatocytes (hepatic steatosis) to hepatic steatosis with inflammation (steatohepatitis), fibrosis, and cirrhosis (1). NAFLD is the most frequent cause of abnormal liver function tests (LFTs) in the US (2, 3), affecting approximately 30 million Americans. Excess hepatic triglyceride accumulation is associated with various drugs, nutritional factors, and multiple genetic defects in energy metabolism. However, the most common disorder associated with hepatic steatosis is insulin resistance (3). As such, it has been proposed that NAFLD be included as a component of the metabolic syndrome (4).

Day et al. (5) initially proposed a “two-hit” model to explain the progression of NAFLD. The “first hit” constitutes the deposition of triglycerides in the cytoplasm of the hepatocyte. The disease does not progress unless additional cellular events occur (the “second hit”) that promote inflammation, cell death, and fibrosis, which are the histologic hallmarks of nonalcoholic steatohepatitis (NASH). Recent studies in animal models of NAFLD have provided new insights into the molecular and physiologic alterations that constitute the first and second hits in the progression of NAFLD to end-stage liver disease and will be the focus of this review.

Acknowledgments

Support for the research cited from the authors’ laboratory was provided by grants from the NIH (HL-20948 and HL-38049) and the Perot Family Foundation. J.D. Horton is a Pew Scholar in the biomedical sciences. J.D. Browning is supported by a post-doctoral fellowship award from the American Liver Foundation and NIH training grant T32-DK-07745. The authors wish to thank Jonathan Cohen, Helen Hobbs, and Joseph Goldstein for critical reading of the manuscript.

Acknowledgments

Footnotes

Nonstandard abbreviations used: acetyl-CoA carboxylase (ACC); AMP-activated protein kinase (AMPK); basic helix-loop-helix-leucine zipper (bHLH-Zip); carbohydrate response element binding protein (ChREBP); carnitine palmitoyl transferase-1 (CPT-1); diethylaminoethoxyhexestrol (DEAEH); liver function test (LFT); liver-type pyruvate kinase (L-PK); malondialdehyde (MDA); mitochondrial respiratory chain (MRC); nonalcoholic fatty-liver disease (NAFLD); nonalcoholic steatohepatitis (NASH); polyunsaturated fatty acid (PUFA); reactive oxygen species (ROS); stearoyl-CoA desaturase (SCD); trans-4-hydroxy-2-nonenal (HNE).

Conflict of interest: The authors have declared that no conflict of interest exists.

Footnotes

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