Molecular Mechanisms and Therapeutic Targets in Steatosis and Steatohepatitis
Pharmacological Reviews
September 2008
vol. 60 no. 3
311-357
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 PPARγ 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.
