Role of Obesity and Lipotoxicity in the Development of Nonalcoholic Steatohepatitis: Pathophysiology and Clinical Implications

Nonalcoholic fatty liver disease (NAFLD), the major reason for abnormal liver function in the Western world, is associated with obesity and diabetes and is characterized by insulin resistance (IR). IR is regulated by mediators released from cells of the immune system or adipocytes and proinflammatory cytokines such as tumor necrosis factor-α (TNFα). The importance of TNFα in human and animal fatty liver diseases, both caused by genetic manipulation and overnutrition, has been shown convincingly. Furthermore, neutralization of TNFα activity improves IR and fatty liver disease in animals. Adiponectin is a potent TNFα-neutralizing and anti-inflammatory adipokine and in vitro and experimental animal studies have proven the importance of this mediator in counteracting inflammation and IR. Anti-inflammatory effects of adiponectin are exerted both by suppressing TNFα synthesis and by induction of anti-inflammatory cytokines such as interleukin-10 or interleukin-1–receptor antagonist. Therefore, the balance between various mediators, either derived from the immune system or adipose tissue, appears to play an important role in hepatic and systemic insulin action and in the development of fatty liver disease.

Alcoholic Liver Disease: Pathogenesis and New Therapeutic Targets

Ferritin, metabolic syndrome and NAFLD: Elective attractions and dangerous liaisons

Common Genetic Variants and Nonalcoholic Fatty Liver Disease

Combined alcoholic and non-alcoholic steatohepatitis.

Focus

Non-alcoholic steatohepatitis: The role of oxidized low-density lipoproteins

Nuclear Factor-κB in the Liver: Friend or Foe?

Variants in Autophagy Genes Affect Susceptibility to Both Crohn's Disease and Helicobacter pylori Infection

Lipin 1 plays a crucial role in lipid metabolism in adipose tissue, skeletal muscle, and liver. Its physiological role involves two cellular functions: regulation of phosphatidate phosphatase activity and regulation of fatty acid oxidation. In this study, we have demonstrated that lipin 1 gene (LPIN1) expression is regulated by cellular sterols, which are key regulators of lipid metabolism. We have also characterized the sterol-response element and nuclear factor Y-binding sites in the human LPIN1 promoter. Using a luciferase assay, electrophoretic mobility shift assay, and chromatin immunoprecipitation assay, we demonstrated that these elements are responsible for the transcription of LPIN1 gene, mediated by SREBP-1 (sterol regulatory element-binding protein 1) and nuclear factor Y. Furthermore, we investigated whether lipin 1 is involved in lipogenesis by transfection of LPIN1 small interfering RNA. We infer that sterol-mediated regulation of lipin 1 gene transcription modulates triglyceride accumulation. This modulation involves changes in the activity of phosphatidate phosphatase.

Are nitric oxide synthases new players in the pathophysiology of fulminant hepatic failure?

Insulin Resistance: Cause or Consequence of Nonalcoholic Steatohepatitis?

From Fat to Inflammation

Impaired Autophagy Triggers Chronic Pancreatitis: Lessons From Pancreas-Specific Atg5 Knockout Mice

Irisin in humans: recent advances and questions for future research