Previous estimates of the prevalence of nonalcoholic fatty liver disease (NAFLD) in the US population relied on measures of liver enzymes, potentially underestimating the burden of this disease. We used ultrasonography data from 12,454 adults who participated in the Third National Health and Nutrition Examination Survey, conducted in the United States from 1988 to 1994. We defined NAFLD as the presence of hepatic steatosis on ultrasonography in the absence of elevated alcohol consumption. In the US population, the rates of prevalence of hepatic steatosis and NAFLD were 21.4% and 19.0%, respectively, corresponding to estimates of 32.5 (95% confidence interval: 29.9, 35.0) million adults with hepatic steatosis and 28.8 (95% confidence interval: 26.6, 31.2) million adults with NAFLD nationwide. After adjustment for age, income, education, body mass index (weight (kg)/height (m)²), and diabetes status, NAFLD was more common in Mexican Americans (24.1%) compared with non-Hispanic whites (17.8%) and non-Hispanic blacks (13.5%) (P = 0.001) and in men (20.2%) compared with women (15.8%) (P < 0.001). Hepatic steatosis and NAFLD were also independently associated with diabetes, with insulin resistance among people without diabetes, with dyslipidemia, and with obesity. Our results extend previous national estimates of the prevalence of NAFLD in the US population and highlight the burden of this disease. Men, Mexican Americans, and people with diabetes and obesity are the most affected groups.

The lipid content of hepatocytes is regulated by the integrated activities of cellular enzymes that catalyze lipid uptake, synthesis, oxidation, and export. When "input" of fats into these systems (either because of increased fatty acid delivery, hepatic fatty acid uptake, or fatty acid synthesis) exceeds the capacity for fatty acid oxidation or export (i.e., "output"), then hepatic steatosis occurs. Genetic causes of increased fatty acid input promote excessive hepatic lipogenesis. These include mutations that cause leptin deficiency or leptin receptor inhibition and mutations that induce insulin, insulin-like growth factors, or insulin-responsive transcription factors. Genetic causes of impaired hepatic fatty acid oxidation inhibit the elimination (i.e., output) of fat from the liver. These include mutations that inhibit various components of the peroxisomal and/or mitochondrial pathways for fatty acid beta-oxidation. Environmental factors, such as diets and toxins, can also unbalance hepatic fatty acid synthesis and oxidation. Hepatic lipogenesis is increased by dietary sucrose, fructose, or fats and certain toxins, such as ethanol. Hepatic fatty acid oxidation is inhibited by choline- or methionine-deficient diets and other toxins, such as etomoxir. Animals with genetic or environmental induction of hepatic lipogenesis appear to be useful models for human nonalcoholic fatty liver disease in which hyperinsulinemia and defective leptin signaling are conspicuous at early stages of the disease process.

Liver fibrosis is a progressive pathologic process that involves deposition of excess extracellular matrix leading to distorted architecture and culminating in cirrhosis. The role of transforming growth factor-␤ (TGF-␤) as a key molecule in the development and progression of hepatic fibrosis via the activation of hepatic stellate cells, among other fibroblast populations, is without controversy. We hereby show that TGF-␤1 induces an epithelial-to-mesenchymal transition (EMT) state in mature hepatocytes in vitro. EMT state was marked by significant upregulation of ␣ 1 (I) collagen mRNA expression and type I collagen deposition. Similar changes were found in a "normal" mouse hepatocyte cell line (AML12), thus confirming that hepatocytes are capable of EMT changes and type I collagen synthesis. We also show that in hepatocytes in the EMT state, TGF-␤1 induces the snail-1 transcription factor and activates the Smad2/3 pathway. Evidence for a central role of the TGF-␤1/Smad pathway is further supported by the inhibition of EMT by Smad4 silencing using small interference RNA technology. In conclusion, TGF-␤1, a known pro-apoptotic cytokine in mature hepatocytes, is capable of mediating phenotypic changes and plasticity in the form of EMT, resulting in collagen deposition. Our findings support a potentially crucial role for EMT in the development and progression of hepatic fibrogenesis.Liver fibrosis results from increased deposition of type I collagen within the hepatic extracellular space and constitutes a common cardinal signature to all forms of liver injury, regardless of etiology (1). End-stage liver fibrosis is recognized clinically as cirrhosis. Since their initial description, hepatic stellate cells (HSC) 3 have dominated the field of liver fibrogenesis (2-4). Indeed, their role is central in hepatic fibrosis (5). Unfortunately, despite several discoveries pertaining to HSC activation and mechanisms of collagen deposition, no substantial anti-fibrotic therapies have been developed in order to halt the progression to cirrhosis and or reverse established fibrosis. Although resident tissue fibroblasts are traditionally considered as the principal source of fibrosis, there has been increasing interest in the ability of epithelial cells to assume not only a mesenchymal phenotype (known as epithelial-to-mesenchymal transition (EMT)) but also to undertake mesenchymal function(s), i.e. contribute to fibrosis formation. Indeed, EMT has been established as a major mechanism for the deposition of extracellular matrix in renal and pulmonary fibrosis injury models (6 -8).Several lines of evidence support an important role for TGF-␤1 signaling in the initiation and progression of liver fibrosis (9). In mature (i.e. adult) hepatocytes, TGF-␤1 is responsible for inhibition of cell proliferation and induction of apoptosis (10 -12). Interestingly, TGF-␤1 is the most established mediator and regulator of EMT (13). It has been shown that TGF-␤1 mediates EMT by inducing snail-1 transcription factor and tyrosine phosphorylation o...

NAFLD patients have decreased serum 25(OH)D concentrations, suggesting that vitamin D may play a role in the development of NAFLD. The directionality of this association cannot be determined from cross-sectional studies. Demonstration of a causal role of hypovitaminosis D in NAFLD development in future studies could have important therapeutic implications.