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0031-6997/08/6003-311-357$7.00
Pharmacol Rev 60:311-357, 2008

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Molecular Mechanisms and Therapeutic Targets in Steatosis and Steatohepatitis

Nora Anderson and Jürgen Borlak

Medical School of Hannover, Center Pharmacology and Toxicology, Hannover, Germany; and Fraunhofer Institute of Toxicology and Experimental Medicine, Hannover, Germany

Abstract
I. Introduction: Hepatic Steatosis—A Common Road with Different Entrances
II. Molecular Mechanisms in the Pathogenesis of Nonalcoholic Hepatic Steatosis and Steatohepatitis
    A. Impaired Insulin Signaling and Reduced Insulin Sensitivity as a Molecular Cause for Steatosis?
    B. Lipid Droplets—Metabolically Active Sites in Hepatic Steatosis?
        1. Lipid Droplet Formation.
        2. PAT Proteins, Insulin Resistance, and Lipid Droplet Breakdown.
        3. PAT Proteins and PPARgamma in Hepatic Steatosis.
        4. Lipid Droplets and Cell Signaling.
        5. Lipid Droplets as a Connective Network.
    C. The Role of Fatty Acids in Steatosis
        1. Fatty Acids as Regulators of Lipogenic Gene Expression.
        2. Polyunsaturated Fatty Acids in Nonalcoholic Hepatic Steatosis and Steatohepatitis.
        3. Therapeutic Effects of Polyunsaturated Fatty Acids in Nonalcoholic Hepatic Steatosis and Steatohepatitis.
        4. Roles for Saturated and Monounsaturated Fatty Acids in Nonalcoholic Hepatic Steatosis and Steatohepatitis.
    D. Molecular Causes Resulting in Steatohepatitis
        1. Nuclear Receptors and Transcription Factors in Steatosis/Nonalcoholic Hepatic Steatosis and Steatohepatitis.
        2. Lipotoxicity as a Mechanism of Steatohepatitis.
        3. Nonalcoholic Hepatic Steatosis and Steatohepatitis—A Lipid Storage Disease?
        4. Organelle Toxicity in Nonalcoholic Hepatic Steatosis and Steatohepatitis.
        5. Microsomal Monooxygenases in Nonalcoholic Fatty Liver Diseases.
        6. Endoplasmic Reticulum in Steatosis.
        7. Endocrine Mediators and Signaling Networks in Hepatic Steatosis.
    E. Molecular Switches between Steatosis and Steatohepatitis
        1. Cross-Talk of Hepatocytes with Stellate Cells, Fibroblasts, Endothelial, and Kupffer Cells in Progressive Liver Disease.
        2. The Role of Arachidonic Acid, Cyclooxygenase II, and Arachidonic Acid Metabolites in Progressive Steatotic Liver Disease.
III. Therapeutic Interventions
    A. Diets and Insulin-Sensitizing Therapies
        1. Weight Loss to Ameliorate Nonalcoholic Hepatic Steatosis and Steatohepatitis.
        2. Insulin Sensitizers in the Therapy of Nonalcoholic Hepatic Steatosis and Steatohepatitis.
    B. Lipid-Lowering Agents and Bile Acid Substitution in the Therapy of Nonalcoholic Hepatic Steatosis and Steatohepatitis
    C. Other Approaches
    D. Novel Targets for Therapeutic Intervention in Nonalcoholic Hepatic Steatosis and Steatohepatitis
IV. Conclusion
Steatosis of the liver may arise from a variety of conditions, but the molecular basis for lipid droplet formation is poorly understood. Although a certain amount of lipid storage may even be hepatoprotective, prolonged lipid storage can result in an activation of inflammatory reactions and loss of metabolic competency. Apart from drug-induced steatosis, certain metabolic disorders associated with obesity, insulin resistance, and hyperlipidemia give also rise to nonalcoholic fatty liver diseases (NAFLD). It is noteworthy that advanced stages of nonalcoholic hepatic steatosis and steatohepatitis (NASH) result ultimately in fibrosis and cirrhosis. In this regard, the lipid droplets (LDs) have been discovered to be metabolically highly active structures that play major roles in lipid transport, sorting, and signaling cascades. In particular, LDs maintain a dynamic communication with the endoplasmic reticulum (ER) and the plasma membrane via sphingolipid-enriched domains of the plasma membrane—the lipid rafts. These microdomains frequently harbor receptor tyrosine kinases and other signaling molecules and connect extracellular events with intracellular signaling cascades. Here, we review recent knowledge on the molecular mechanisms of drug and metabolically induced hepatic steatosis and its progression to steatohepatitis (NASH). The contribution of cytokines and other signaling molecules, as well as activity of nuclear receptors, lipids, transcription factors, and endocrine mediators toward cellular dysfunction and progression of steatotic liver disease to NASH is specifically addressed, as is the cross-talk of different cell types in the pathogenesis of NAFLD. Furthermore, we provide an overview of recent therapeutic approaches in NASH therapy and discuss new as well as putative targets for pharmacological interventions.

Address correspondence to: Prof. Dr. Jürgen Borlak, Fraunhofer Institute of Toxicology and Experimental Medicine, Nikolai-Fuchs-Str. 1, 30625 Hannover, Germany. E-mail: borlak{at}item.fraunhofer.de






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