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Nonalcoholic fatty liver disease experiences accumulation of hepatic liquid crystal associated with increasing lipophagy.

ABSTRACT: Background:In the past 30 years, incidences of non-alcoholic fatty liver disease (NAFLD) has risen by 30%. However, there is still no clear mechanism or accurate method of anticipating liver failure. Here we reveal the phase transitions of liquid crystalline qualities in hepatic lipid droplets (HLDs) as a novel method of anticipating prognosis. Methods:NAFLD was induced by feeding C57BL/6J mice on a high-fat (HiF) diet. These NAFLD livers were then evaluated under polarized microscopy, X-ray diffraction and small-angle scattering, lipid component chromatography analysis and protein expression analysis. Optically active HLDs from mouse model and patient samples were both then confirmed to have liquid crystal characteristics. Liver MAP1LC3A expression was then evaluated to determine the role of autophagy in liquid crystal HLD (LC-HLD) formation. Results:Unlike the normal diet cohort, HiF diet mice developed NAFLD livers containing HLDs exhibiting Maltese cross birefringence, phase transition, and fluidity signature to liquid crystals. These LC-HLDs transitioned to anisotropic crystal at 0 °C and remain crystalline. Temperature increase to 42 °C causes both liquid crystal and crystal HLDs to convert to isotropic droplet form. These isotropic HLDs successfully transition to anisotropic LC with fast temperature decrease and anisotropic crystal with slow temperature decrease. These findings were duplicated in patient liver. Patient LC-HLDs with no inner optical activity were discovered, hinting at lipid saturation as the mechanism through which HLD acquire LC characteristics. Downregulation of MAP1LC3A in conjunction with increased LC-HLD also implicated autophagy in NAFLD LC-HLD formation. Conclusions:Increasing concentrations of amphiphilic lipids in HLDs favors organization into alternating hydrophilic and hydrophobic layers, which present as LC-HLDs. Thus, evaluating the extent of liquid crystallization with phase transition in HLDs of NAFLD patients may reveal disease severity and predict impending liver damage.

SUBMITTER: Wang L

PROVIDER: S-EPMC7137450 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Nonalcoholic fatty liver disease experiences accumulation of hepatic liquid crystal associated with increasing lipophagy.

Wang Liyang L Xu MengMeng M Jones Odell D OD Li Zhongguang Z Liang Yu Y Yu Qiuxia Q Li Jiali J Wu Yajun Y Lei Xinjuan X He Boling B Yue Huimin H Xiao Liqin L Zhou Rong R Zhang Wei W Zhou Xin X Zhang Yuhui Y Bryant Joseph L JL Ma Jianjie J Liu Yingli Y Xu Xuehong X

Cell & bioscience 20200406

<h4>Background</h4>In the past 30 years, incidences of non-alcoholic fatty liver disease (NAFLD) has risen by 30%. However, there is still no clear mechanism or accurate method of anticipating liver failure. Here we reveal the phase transitions of liquid crystalline qualities in hepatic lipid droplets (HLDs) as a novel method of anticipating prognosis.<h4>Methods</h4>NAFLD was induced by feeding C57BL/6J mice on a high-fat (HiF) diet. These NAFLD livers were then evaluated under polarized micros ...[more]

PMID: 32280452

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Project description:Nonalcoholic fatty liver disease (NAFLD) plays a crucial role in type 2 diabetes and hepatocellular carcinoma. The major underlying pathogenesis is hepatic insulin resistance. The aim of the present study was to characterize patients with NAFLD with paradoxically normal hepatic insulin sensitivity relative to patients with NAFLD with hepatic insulin resistance. We recruited 26 patients with NAFLD and divided them into three groups ranked by the level of hepatic insulin sensitivity (HIS; high-HIS, mid-HIS, low-HIS), as assessed by the hyperinsulinemic-euglycemic clamp studies using stable isotope. Hepatic insulin sensitivity of the high-HIS group was identical to that of the non-NAFLD lean control (clamped percent suppression of endogenous glucose production, 91.1% ± 5.2% versus 91.0% ± 8.5%, respectively) and was significantly higher than that of the low-HIS group (66.6% ± 7.5%; P < 0.01). Adiposity (subcutaneous, visceral, intrahepatic, and muscular lipid content), hepatic histopathology, and expression levels of various genes by using liver biopsies, muscle, and adipose tissue insulin sensitivity, plasma metabolites by metabolomics analysis, putative biomarkers, and lifestyles were assessed and compared between the high-HIS and low-HIS groups. Among these, adipose tissue insulin sensitivity assessed by clamped percent suppression of free fatty acid, serum high molecular weight adiponectin, and plasma tricarboxylic acid cycle metabolites, such as citric acid and cis-aconitic acid, were significantly higher in the high-HIS group compared to the low-HIS group. In contrast, there were no differences in adiposity, including intrahepatic lipid content assessed by proton magnetic resonance spectroscopy (28.3% ± 16.1% versus 20.4% ± 9.9%, respectively), hepatic histopathology, other putative biomarkers, and lifestyles. Conclusion: High levels of adipose tissue insulin sensitivity, serum high molecular weight adiponectin, and plasma tricarboxylic acid cycle metabolites are unique characteristics that define patients with hepatic insulin-sensitive NAFLD regardless of intrahepatic lipid content. (Hepatology Communications 2017;1:634-647).

Project description:Population-level nonalcoholic fatty liver disease (NAFLD) death rate data are sparse. We described death rates for adults with NAFLD in the United States using mortality data from the National Vital Statistics System multiple-cause mortality data (2007-2016). Decedents who had NAFLD were identified by International Classification of Diseases (ICD) codes K75.81, K76.0, K74.0, K74.6, and K76.9. Among NAFLD decedents, cause-specific deaths (e.g., cardiovascular disease [CVD], cirrhosis, hepatocellular carcinoma [HCC], non-liver cancer, diabetes mellitus [DM]) were identified by underlying cause of death ICD-10 codes. Trends were evaluated by average annual percentage change (AAPC) in age-standardized death rate (ASDR) per 100,000 persons. Among the 25,129,960 decedents aged ≥20 years, 353,234 (1.4%) decedents had NAFLD (212,322 men; 260,765 non-Hispanic whites, 32,868 non-Hispanic blacks, 46,530 Hispanics, 5,025 non-Hispanic American Indian or Alaska Natives [AIANs], 7,023 non-Hispanic Asian or Pacific Islanders [APIs]), with a mean age at death of 64.47 ± 13.17 years. During the study period, the ASDR for NAFLD increased by 15% (12.94 to 14.90; AAPC, 1.98%; P < 0.001]), while women (AAPC, 2.99% vs. 1.16% men; P = 0.003), non-Hispanic whites (AAPC, 2.48%), non-Hispanic AIANs (AAPC, 2.31%), and Hispanics (AAPC, 0.74%) experienced the highest annual increases. Stable trends were noted for non-Hispanic blacks and non-Hispanic APIs. Among subgroups, Mexican (AAPC, 1.75%) and Asian Indians (AAPC, 6.94%) experienced annual increases. The top six underlying causes of death (155,894 cirrhosis, 38,444 CVD, 19,466 non-liver cancer, 10,867 HCC, 8,113 DM, and 5,683 lung disease) accounted for 67.5% of NAFLD-related deaths. For cause-specific deaths, ASDR increased for HCC (AAPC, 3.82%), DM (AAPC, 2.23%), non-liver cancer (AAPC, 2.14%), CVD (AAPC, 1.59%), and cirrhosis (AAPC, 0.96%). Conclusion: NAFLD-related deaths in U.S. adults are increasing. Cirrhosis is the top cause-specific death, followed by CVD. Women, non-Hispanic whites, and non-Hispanic AIANs (subgroups Mexicans and Asian Indians) experienced the highest increases in deaths. Policies addressing the societal burden of NAFLD are needed.

Dataset Information

Nonalcoholic fatty liver disease experiences accumulation of hepatic liquid crystal associated with increasing lipophagy.

Publications

Nonalcoholic fatty liver disease experiences accumulation of hepatic liquid crystal associated with increasing lipophagy.

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