From Fat to Inflammation

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.

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

Mitochondrial free cholesterol loading sensitizes to TNF- and Fas-mediated steatohepatitis

Alcoholic Liver Disease: Pathogenesis and New Therapeutic Targets

Combined alcoholic and non-alcoholic steatohepatitis.

Nonalcoholic Fatty Liver Disease in Children: Where Are We?

Insulin Resistance: Cause or Consequence of Nonalcoholic Steatohepatitis?

The role of the gut microbiome in chronic liver disease: the clinical evidence revised.

Common Genetic Variants and Nonalcoholic Fatty Liver Disease

Adiposity is commonly associated with adipose tissue dysfunction and many overnutrition-related metabolic diseases including type 2 diabetes. Much attention has been paid to reducing adiposity as a way to improve adipose tissue function and systemic insulin sensitivity. PFKFB3/iPFK2 is a master regulator of adipocyte nutrient metabolism. Using PFKFB3(+/-) mice, the present study investigated the role of PFKFB3/iPFK2 in regulating diet-induced adiposity and systemic insulin resistance. On a high-fat diet (HFD), PFKFB3(+/-) mice gained much less body weight than did wild-type littermates. This was attributed to a smaller increase in adiposity in PFKFB3(+/-) mice than in wild-type controls. However, HFD-induced systemic insulin resistance was more severe in PFKFB3(+/-) mice than in wild-type littermates. Compared with wild-type littermates, PFKFB3(+/-) mice exhibited increased severity of HFD-induced adipose tissue dysfunction, as evidenced by increased adipose tissue lipolysis, inappropriate adipokine expression, and decreased insulin signaling, as well as increased levels of proinflammatory cytokines in both isolated adipose tissue macrophages and adipocytes. In an in vitro system, knockdown of PFKFB3/iPFK2 in 3T3-L1 adipocytes caused a decrease in the rate of glucose incorporation into lipid but an increase in the production of reactive oxygen species. Furthermore, knockdown of PFKFB3/iPFK2 in 3T3-L1 adipocytes inappropriately altered the expression of adipokines, decreased insulin signaling, increased the phosphorylation states of JNK and NFkappaB p65, and enhanced the production of proinflammatory cytokines. Together, these data suggest that PFKFB3/iPFK2, although contributing to adiposity, protects against diet-induced insulin resistance and adipose tissue inflammatory response.

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

Changing Epidemiology of Cirrhosis and Hepatic Encephalopathy

Liquid biomarkers for fibrotic NASH – progress in a complex field

Abnormal aminotransferase activity in women with polycystic ovary syndrome