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Concept: Steatosis

184

The impairment of liver function by low environmentally relevant doses of glyphosate-based herbicides (GBH) is still a debatable and unresolved matter. Previously we have shown that rats administered for 2 years with 0.1 ppb (50 ng/L glyphosate equivalent dilution; 4 ng/kg body weight/day daily intake) of a Roundup GBH formulation showed signs of enhanced liver injury as indicated by anatomorphological, blood/urine biochemical changes and transcriptome profiling. Here we present a multiomic study combining metabolome and proteome liver analyses to obtain further insight into the Roundup-induced pathology. Proteins significantly disturbed (214 out of 1906 detected, q < 0.05) were involved in organonitrogen metabolism and fatty acid β-oxidation. Proteome disturbances reflected peroxisomal proliferation, steatosis and necrosis. The metabolome analysis (55 metabolites altered out of 673 detected, p < 0.05) confirmed lipotoxic conditions and oxidative stress by showing an activation of glutathione and ascorbate free radical scavenger systems. Additionally, we found metabolite alterations associated with hallmarks of hepatotoxicity such as γ-glutamyl dipeptides, acylcarnitines, and proline derivatives. Overall, metabolome and proteome disturbances showed a substantial overlap with biomarkers of non-alcoholic fatty liver disease and its progression to steatohepatosis and thus confirm liver functional dysfunction resulting from chronic ultra-low dose GBH exposure.

Concepts: Steatosis, Oxidative stress, Radical, Non-alcoholic fatty liver disease, Roundup, Fatty liver, Antioxidant, Metabolism

175

Data on cardiac function in patients with nonalcoholic fatty liver disease (NAFLD) are limited and conflicting. We assessed whether NAFLD is associated with abnormalities in cardiac function in patients with type 2 diabetes.

Concepts: Steatosis, Non-alcoholic fatty liver disease, Metabolic syndrome, Fatty liver, Obesity

165

Nuciferine is a major active aporphine alkaloid from the leaves of N. nucifera Gaertn that possesses anti-hyperlipidemia, anti-hypotensive, anti-arrhythmic, and insulin secretagogue activities. However, it is currently unknown whether nuciferine can benefit hepatic lipid metabolism.

Concepts: Steatosis, Protein, Fat, Obesity, Glycogen

158

The development of non-alcoholic fatty liver disease (NAFLD) is a multiple step process. Here, we show that activation of cdk4 triggers the development of NAFLD. We found that cdk4 protein levels are elevated in mouse models of NAFLD and in patients with fatty livers. This increase leads to C/EBPα phosphorylation on Ser193 and formation of C/EBPα-p300 complexes, resulting in hepatic steatosis, fibrosis, and hepatocellular carcinoma (HCC). The disruption of this pathway in cdk4-resistant C/EBPα-S193A mice dramatically reduces development of high-fat diet (HFD)-mediated NAFLD. In addition, inhibition of cdk4 by flavopiridol or PD-0332991 significantly reduces development of hepatic steatosis, the first step of NAFLD. Thus, this study reveals that activation of cdk4 triggers NAFLD and that inhibitors of cdk4 may be used for the prevention/treatment of NAFLD.

Concepts: Steatohepatitis, Metabolic syndrome, Cancer, Obesity, Steatosis, Cirrhosis, Non-alcoholic fatty liver disease, Fatty liver

142

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease whose prevalence has reached global epidemic proportions. Although the disease is relatively benign in the early stages, when severe clinical forms, including nonalcoholic steatohepatitis (NASH), cirrhosis and even hepatocellular carcinoma, occur, they result in worsening the long-term prognosis. A growing body of evidence indicates that NAFLD develops from a complex process in which many factors, including genetic susceptibility and environmental insults, are involved. In this review, we focused on the genetic component of NAFLD, with special emphasis on the role of genetics in the disease pathogenesis and natural history. Insights into the topic of the genetic susceptibility in lean individuals with NAFLD and the potential use of genetic tests in identifying individuals at risk are also discussed.

Concepts: Steatosis, Hepatitis, Cirrhosis, Fatty liver, Non-alcoholic fatty liver disease

139

Background and Aims: There has been increasing evidence that vitamin D deficiency may increase the risk of metabolic syndrome. Since metabolic syndrome is a major risk factor for non-alcoholic fatty liver disease (NAFLD), we aimed to investigate the association between vitamin D and the severity and mortality of NAFLD. Methods: Data was obtained from the United States Third National Health and Nutrition Examination Survey conducted in 1988-1994, with follow-up mortality data through 2011. NAFLD was defined by ultrasonographic detection of hepatic steatosis in the absence of other liver diseases and categorized as normal, mild, moderate or severe. The severity of hepatic fibrosis was determined by NAFLD fibrosis score (NFS). ANOVA (F-test) was used to evaluate the association between vitamin D level and degree of NAFLD, and Cox proportional hazards regression analysis was used for survival analyses. Results: Vitamin D levels for normal, mild, moderate and severe steatosis were 25.1 ± 0.29 ng/mL, 24.7 ± 0.42 ng/mL, 23.7 ± 0.37 ng/mL and 23.6 ± 0.60 ng/mL, respectively (trend p < 0.001). Likewise, vitamin D levels for low, intermediate and high NFS categories were 24.7 ± 0.38 ng/mL, 23.4 ± 0.42 ng/mL and 21.5 ± 0.57 ng/mL, respectively (trend p < 0.001). After median-follow up over 19 years, vitamin D deficiency was significantly associated with diabetes- and Alzheimer's disease-related mortality (hazard ratio (HR): 3.64, 95%CI: 1.51-8.82 and HR: 4.80, 95%CI: 1.53-15.1, respectively), with a borderline significance in overall mortality (HR: 1.16, 95%CI: 0.99-1.36, p = 0.06). Conclusions: Vitamin D level was inversely related to the degree of liver steatosis and fibrosis. Moreover, vitamin D deficiency was associated with diabetes- and Alzheimer's disease-related mortality in NAFLD patients.

Concepts: Nutrition, Cirrhosis, Metabolic syndrome, Obesity, Vitamin D, Non-alcoholic fatty liver disease, Steatosis, Fatty liver

126

The hepatic manifestation of metabolic syndrome is nonalcoholic fatty liver disease. Patients with nonalcoholic steatohepatitis, the progressive form of nonalcoholic fatty liver disease, have increased risk of fibrosis, cirrhosis and end-stage liver disease. Estimates of prevalence in the United States range from 20-30 % for nonalcoholic fatty liver disease and 2-5 % for nonalcoholic steatohepatitis; however, physician awareness of these diseases is limited. The purpose of this study was to determine the current level of physician awareness and practices in the diagnosis and management of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis within the United States.

Concepts: Steatohepatitis, Hepatitis, Steatosis, Obesity, Metabolic syndrome, Cirrhosis, Fatty liver, Non-alcoholic fatty liver disease

43

Nonalcoholic fatty liver disease (NAFLD) is a major public health burden in western societies. The progressive form of NAFLD, nonalcoholic steatohepatitis (NASH), is characterized by hepatosteatosis, inflammation, oxidative stress, and hepatic damage that can progress to fibrosis and cirrhosis; risk factors for hepatocellular carcinoma. Given the scope of NASH, validating treatment protocols (i.e., low fat diets and weight loss) is imperative.

Concepts: Cancer, Hepatitis, Steatosis, Metabolic syndrome, Obesity, Cirrhosis, Fatty liver, Non-alcoholic fatty liver disease

33

Nonalcoholic fatty liver disease (NAFLD) is a major public health concern in western societies. Nonalcoholic steatohepatitis (NASH), the progressive form of NAFLD, is characterized by hepatic steatosis, inflammation, oxidative stress and fibrosis. NASH is a risk factor for cirrhosis and hepatocellular carcinoma. NASH is predicted to be the leading cause of liver transplants by 2020. Despite this growing public health concern, there remain no Food and Drug Administration (FDA) approved NASH treatments. Using Ldlr -/- mice as a preclinical model of western diet (WD)-induced NASH, we previously established that dietary supplementation with docosahexaenoic acid (DHA, 22:6,ω3) attenuated WD-induced NASH in a prevention study. Herein, we evaluated the capacity of DHA supplementation of the WD and a low fat diet to fully reverse NASH in mice with pre-existing disease.

Concepts: Hepatitis, Nutrition, Steatosis, Metabolic syndrome, Cirrhosis, Obesity, Fatty liver, Non-alcoholic fatty liver disease

29

The incidence of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) has increased in parallel with the incidence of obesity. While both NAFLD and NASH are characterized by hepatosteatosis, NASH is characterized by hepatic damage, inflammation, oxidative stress, and fibrosis. We previously reported that feeding Ldlr(-/-) mice a high-fat, high-cholesterol diet containing menhaden oil attenuated several markers of NASH, including hepatosteatosis, inflammation, and fibrosis. Herein, we test the hypothesis that DHA [22:6 (n-3)] is more effective than EPA [20:5 (n-3)] at preventing Western diet (WD)-induced NASH in Ldlr(-/-) mice. Mice were fed the WD supplemented with either olive oil (OO), EPA, DHA, or EPA + DHA for 16 wk. WD + OO feeding induced a severe NASH phenotype, characterized by robust hepatosteatosis, inflammation, oxidative stress, and fibrosis. Whereas none of the C20-22 (n-3) fatty acid treatments prevented WD-induced hepatosteatosis, all 3 (n-3) PUFA-containing diets significantly attenuated WD-induced inflammation, fibrosis, and hepatic damage. The capacity of dietary DHA to suppress hepatic markers of inflammation (Clec4F, F4/80, Trl4, Trl9, CD14, Myd88), fibrosis (Procol1α1, Tgfβ1), and oxidative stress (NADPH oxidase subunits Nox2, p22phox, p40phox, p47phox, p67phox) was significantly greater than dietary EPA. The effects of DHA on these markers paralleled DHA-mediated suppression of hepatic Fads1 mRNA abundance and hepatic arachidonic acid content. Because DHA suppression of NASH markers does not require a reduction in hepatosteatosis, dietary DHA may be useful in combating NASH in obese humans.

Concepts: Eicosapentaenoic acid, Steatosis, Omega-3 fatty acid, Nutrition, Metabolic syndrome, Obesity, Non-alcoholic fatty liver disease, Fatty liver