15 Inhibition of triglyceride synthesis via DGAT2 antisense oligonucleotides improves liver steatosis but worsens beta-catenin inhibitor liver damage, also suggesting that accumulation of liver triglycerides could be a protective mechanism.16 Hepatic steatosis (i.e., triglyceride accumulation) is dissociated from insulin resistance in patients with familial hypobetalipoproteinemia, providing

further evidence that increased intrahepatic triglyceride content might be more a marker rather than a cause of insulin resistance.17 In summary, triglyceride synthesis seems to be an adaptive, beneficial response in situations where hepatocytes are exposed to potentially toxic triglyceride metabolites. Thus, evidence is increasing that accumulation of fat in the liver in Mitomycin C cell line many instances cannot be regarded as a pathology or disease,

but rather as a physiologic response to increased caloric consumption.18 Free fatty acids and cholesterol, especially when accumulated in mitochondria, are considered the “aggressive” lipids leading to tumor necrosis factor alpha (TNFα)-mediated liver damage and reactive oxygen species (ROS) formation.19, 20 These lipids could also be present in a nonsteatotic liver and act as early “inflammatory” hits leading to the whole spectrum of NAFLD pathologies. The concept of lipotoxicity and involved lipid species has been introduced and discussed in several excellent review articles.21, 22 Simple

hepatic steatosis, which is benign and nonprogressive in the majority of patients, and NASH may reflect different disease entities. Inflammation results in a stress response of hepatocytes, may lead to lipid accumulation, and therefore could precede steatosis in NASH. Such a cascade is supported by various studies. Patients with NASH may present see more without any or much steatosis, suggesting that inflammation could take place first.1 Anti-TNF antibody treatment and metformin, an antidiabetic drug that inhibits hepatic TNFα expression, improve steatosis in ob/ob mice.23, 24 Other proinflammatory mediators might also contribute to the development of steatosis because in some studies hepatic steatosis was not dependent on TNFα.25, 26 In patients with severe alcoholic hepatitis, treatment with infliximab, an anti-TNF antibody, primarily improves hepatic steatosis.27 Loss of Kupffer cells also leads to hepatic steatosis probably via decreased interleukin-10 (IL-10) release from Kupffer cells.28 Other cell types might also promote hepatic steatosis because obesity leads to the hepatic recruitment of a myeloid cell population that further promotes hepatic lipid storage.29 In all these situations, hepatic steatosis may be considered as “bystander phenomenon” subsequent to inflammatory attacks.