Dataset Information

Differential effects of reticulophagy and mitophagy on nonalcoholic fatty liver disease.

ABSTRACT: Autophagy affects the pathological progression of non-alcoholic fatty liver disease (NAFLD); however, the precise role of autophagy in NAFLD remains unclear. In this study, we want to identify the role of autophagy including reticulophagy and mitophagy in NAFLD pathogenesis. When HepG2 cells were treated with 400??M oleic acid (OA), increased reticulophagy was induced 8?h after treatment, which correlated with an anti-apoptotic response as shown by the activation of the PI3K/AKT pathway, an increase in BCL-2 expression, and the downregulation of OA-induced lipotoxicity. When treated with OA for 24?h, DRAM expression-dependent mitophagy resulted in increased apoptosis in HepG2 cells. Inhibition of reticulophagy aggravated and increased lipotoxicity-induced apoptosis 8?h after treatment; however, the inhibition of mitophagy decreased hepatocyte apoptosis after 24?h of OA treatment. Results from the analysis of patient liver samples showed that autophagic flux increased in patients with mild or severe NAFL. PI3K/AKT phosphorylation was observed only in samples from patients with low-grade steatosis, whereas DRAM expression was increased in samples from patients with high-grade steatosis. Together, our results demonstrate that reticulophagy and mitophagy are independent, sequential events that influence NAFLD progression, which opens new avenues for investigating new therapeutics in NAFLD.

SUBMITTER: Pang L

PROVIDER: S-EPMC5833629 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

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Differential effects of reticulophagy and mitophagy on nonalcoholic fatty liver disease.

Pang Lijun L Liu Kai K Liu Daojie D Lv Fudong F Zang Yunjin Y Xie Fang F Yin Jiming J Shi Ying Y Wang Yanjun Y Chen Dexi D

Cell death & disease 20180124 2

Autophagy affects the pathological progression of non-alcoholic fatty liver disease (NAFLD); however, the precise role of autophagy in NAFLD remains unclear. In this study, we want to identify the role of autophagy including reticulophagy and mitophagy in NAFLD pathogenesis. When HepG2 cells were treated with 400 μM oleic acid (OA), increased reticulophagy was induced 8 h after treatment, which correlated with an anti-apoptotic response as shown by the activation of the PI3K/AKT pathway, an incr ...[more]

PMID: 29367738

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Project description:Based on the assumption that characterizing the history of a disease will help in improving practice while offering a clue to research, this article aims at reviewing the history of nonalcoholic fatty liver disease (NAFLD) in adults and children. To this end, we address the history of NAFLD histopathology, which begins in 1980 with Ludwig's seminal studies, although previous studies date back to the 19th century. Moreover, the principal milestones in the definition of genetic NAFLD are summarized. Next, a specific account is given of the evolution, over time, of our understanding of the association of NAFLD with metabolic syndrome, spanning from the outdated concept of "NAFLD as a manifestation of the Metabolic Syndrome", to the more appropriate consideration that NAFLD has, with metabolic syndrome, a mutual and bi-directional relationship. In addition, we also report on the evolution from first intuitions to more recent studies, supporting NAFLD as an independent risk factor for cardiovascular disease. This association probably has deep roots, going back to ancient Middle Eastern cultures, wherein the liver had a significance similar to that which the heart holds in contemporary society. Conversely, the notions that NAFLD is a forerunner of hepatocellular carcinoma and extra-hepatic cancers is definitely more modern. Interestingly, guidelines issued by hepatological societies have lagged behind the identification of NAFLD by decades. A comparative analysis of these documents defines both shared attitudes (e.g., ultrasonography and lifestyle changes as the first approaches) and diverging key points (e.g., the threshold of alcohol consumption, screening methods, optimal non-invasive assessment of liver fibrosis and drug treatment options). Finally, the principal historical steps in the general, cellular and molecular pathogenesis of NAFLD are reviewed. We conclude that an in-depth understanding of the history of the disease permits us to better comprehend the disease itself, as well as to anticipate the lines of development of future NAFLD research.

Project description:Nonalcoholic fatty liver disease (NAFLD) is the most common liver disorder in the United States; however, few data are available about racial and ethnic variation. We investigated relationships between ethnicity, NAFLD severity, metabolic derangements, and sociodemographic characteristics in a well-characterized cohort of adults with biopsy-proven NAFLD. Data were analyzed from 1,026 adults (?18 years) in the Nonalcoholic Steatohepatitis Clinical Research Network (NASH CRN) from 2004 to 2008, for whom liver histology data were available within 6 months of enrollment. Associations between ethnicity (i.e., Latino versus non-Latino white) and NAFLD severity (i.e., NASH versus non-NASH histology and mild versus advanced fibrosis) were explored with multiple logistic regression analysis. We also investigated effect modification of ethnicity on metabolic derangements for NAFLD severity. Within the NASH CRN, 77% (N = 785) were non-Latino white and 12% (N = 118) were Latino. Sixty-one percent (N = 628) had NASH histology and 28% (N = 291) had advanced fibrosis. Latinos with NASH were younger, performed less physical activity, and had higher carbohydrate intake, compared to non-Latino whites with NASH. Gender, diabetes, hypertension, hypertriglyceridemia, aspartate aminotransferase (AST), platelets, and the homeostasis model assessment of insulin resistance (HOMA-IR) were significantly associated with NASH. Age, gender, AST, alanine aminotransferase, alkaline phosphatase, platelets, total cholesterol, hypertension, and HOMA-IR, but not ethnicity, were significantly associated with advanced fibrosis. The effect of HOMA-IR on the risk of NASH was modified by ethnicity: HOMA-IR was not a significant risk factor for NASH among Latinos (odds ratio [OR] = 0.93; 95% confidence interval [CI]: 0.85-1.02), but was significant among non-Latino whites (OR, 1.06; 95% CI: 1.01-1.11).Metabolic risk factors and sociodemographic characteristics associated with NASH differ by ethnicity. Additional insights into NASH pathogenesis may come from further studies focused on understanding ethnic differences in this disease.

Dataset Information

Differential effects of reticulophagy and mitophagy on nonalcoholic fatty liver disease.

Publications

Differential effects of reticulophagy and mitophagy on nonalcoholic fatty liver disease.

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