Using the NHANES III database, Liangpunsakul and Chalasani[34] re

Using the NHANES III database, Liangpunsakul and Chalasani[34] reviewed over 6,800 patients and found 308 with unexplained elevation in alanine aminotransferase (ALT) and compared their serum vitamin D concentrations with

those of 979 matched controls. NHANES III Galunisertib research buy patients with elevated ALT were found to have lower vitamin D levels than the control group, even when controlling for metabolic syndrome, IR, and serum triglyceride level. This was confirmed in a study of 262 patients referred to an endocrinology clinic where the relationship between NAFLD and reduced vitamin D levels persisted regardless of age, sex, triglycerides, and IR.[35] Targher et al.[36] confirmed the association between NAFLD and VDD and importantly evaluated the relationship of liver histology to vitamin D levels. Vitamin D concentrations were lower in NASH patients when compared to those with isolated fatty liver and inversely correlated with liver histology. The understanding of NASH pathogenesis has evolved from the relatively simplistic “two-hit” hypothesis and includes a number of metabolic Temozolomide pathways resulting in hepatic steatosis, steatohepatitis, and hepatic fibrosis. A number of these pathways can be affected by vitamin D and relate to the hormonal, immunologic, and cellular differentiation “nonclassical” effects

of vitamin D. Hepatic steatosis is generally thought to arise from lipolysis derived flux of free fatty acids (FFA) from adipocytes, as well as dietary lipids, de novo lipogenesis, and impaired lipid disposal.[37] The buildup of FFA results in insulin signaling defects and impairment of cellular glucose metabolism, with the resulting hyperglycemia leading to increased lipogenesis through increased activation of sterol regulatory element binding proteins (SREBP)[38] as well as activation of carbohydrate response element binding proteins (CHREBP).[39] Visceral adipose tissue also plays an important role in a variety of inflammatory and immune reactions pertinent to NASH by way of secretion of adipocytokines such as adiponectin, resistin, and omentin.[40] Adiponectin has been described as the prototypic adipocytokine

medchemexpress by way of its function as an antiinflammatory agent.[41] Low adiponectin levels are independently associated with obesity and NASH[42] and adiponectin levels increase after weight loss.[43] In murine models, high levels of adiponectin have been experimentally shown to decrease necroinflammation and steatosis in alcoholic and nonalcoholic fatty liver disease,[44] as well as improved insulin resistance,[45] suggesting that, in humans, adiponectin may improve hepatic inflammation and hepatic insulin sensitivity.[46] Indeed, data suggest that when pioglitazone is given to NASH patients, adiponectin levels increase 2-fold to 3-fold with an associated improvement in IR as well as improved steatosis, necroinflammation, and fibrosis.

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