Analysis of Common Pathways and Markers From Non-Alcoholic Fatty Liver Disease to Immune-Mediated Diseases

Metabolic associated fatty liver disease (MAFLD) is the most prevalent form of liver disease worldwide, accounting for a high liver-related mortality and morbidity with extensive multi-organ involvement. This entity has displaced viral hepatitis as the main cause of severe forms of hepatic diseases, although the onset and transition of MAFLD stages still remains unclear. Nevertheless, innate and adaptive immune responses seem to play an essential role in the establishment and further progression of this disease. The immune system is responsible of safeguard and preserves organs and systems function, and might be altered under different stimuli. Thus, the liver suffers from metabolic and immune changes leading to different injuries and loss of function. It has been stablished that cell-cell crosstalk is a key process in the hepatic homeostasis maintenance. There is mounting evidence suggesting that MAFLD pathogenesis is determined by a complex interaction of environmental, genetic and host factors that leads to a full plethora of outcomes. Therefore, herein we will revisit and discuss the interplay between immune mechanisms and MAFLD, highlighting the potential role of immunological markers in an attempt to clarify its relationship.

Download Full-text

Obesity-linked suppression of membrane-bound O-acyltransferase 7 (MBOAT7) drives non-alcoholic fatty liver disease

eLife ◽

10.7554/elife.49882 ◽

2019 ◽

Vol 8 ◽

Cited By ~ 20

Author(s):

Robert N Helsley ◽

Venkateshwari Varadharajan ◽

Amanda L Brown ◽

Anthony D Gromovsky ◽

Rebecca C Schugar ◽

...

Keyword(s):

Liver Disease ◽

Fatty Liver ◽

Fatty Liver Disease ◽

Dependent Manner ◽

Loss Of Function ◽

Alcoholic Fatty Liver ◽

Hepatic Expression ◽

Increased Risk ◽

Membrane Bound ◽

Alcoholic Fatty Liver Disease

Recent studies have identified a genetic variant rs641738 near two genes encoding membrane bound O-acyltransferase domain-containing 7 (MBOAT7) and transmembrane channel-like 4 (TMC4) that associate with increased risk of non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), alcohol-related cirrhosis, and liver fibrosis in those infected with viral hepatitis (Buch et al., 2015; Mancina et al., 2016; Luukkonen et al., 2016; Thabet et al., 2016; Viitasalo et al., 2016; Krawczyk et al., 2017; Thabet et al., 2017). Based on hepatic expression quantitative trait loci analysis, it has been suggested that MBOAT7 loss of function promotes liver disease progression (Buch et al., 2015; Mancina et al., 2016; Luukkonen et al., 2016; Thabet et al., 2016; Viitasalo et al., 2016; Krawczyk et al., 2017; Thabet et al., 2017), but this has never been formally tested. Here we show that Mboat7 loss, but not Tmc4, in mice is sufficient to promote the progression of NAFLD in the setting of high fat diet. Mboat7 loss of function is associated with accumulation of its substrate lysophosphatidylinositol (LPI) lipids, and direct administration of LPI promotes hepatic inflammatory and fibrotic transcriptional changes in an Mboat7-dependent manner. These studies reveal a novel role for MBOAT7-driven acylation of LPI lipids in suppressing the progression of NAFLD.

Download Full-text

Auranofin Attenuates Non-Alcoholic Fatty Liver Disease by Suppressing Lipid Accumulation and NLRP3 Inflammasome-Mediated Hepatic Inflammation In Vivo and In Vitro

Antioxidants ◽

10.3390/antiox9111040 ◽

2020 ◽

Vol 9 (11) ◽

pp. 1040

Author(s):

Hyun Hwangbo ◽

Min Yeong Kim ◽

Seon Yeong Ji ◽

So Young Kim ◽

Hyesook Lee ◽

...

Keyword(s):

Liver Disease ◽

Fatty Liver ◽

Nlrp3 Inflammasome ◽

Lipid Accumulation ◽

Fatty Liver Disease ◽

Hepatic Inflammation ◽

Alcoholic Fatty Liver ◽

Hepatic Diseases ◽

Alcoholic Fatty Liver Disease

Non-alcoholic fatty liver disease (NAFLD) causes liver dysfunction and is associated with obesity and type 2 diabetes. Chronic inflammation is associated not only with the development of NAFLD, but also with hepatic diseases, including steatohepatitis, cirrhosis, and hepatocellular carcinoma. Auranofin is a treatment for rheumatoid arthritis and has recently been reported to have potential effects against a variety of diseases, including inflammation, cancer, and viral infection. In this study, auranofin may be considered as a new treatment for the management of metabolic syndrome, as well as in the treatment of NAFLD through immunomodulation. To determine the effect of auranofin on NAFLD, C57BL/6 mice were randomly grouped, fed a regular diet or a high fat diet (HFD), and injected with normal saline or auranofin for 8 weeks. Auranofin significantly decreased the body weight, epididymal fat weight, serum aspartate aminotransferase (AST), and glucose, as well as the serum triglyceride, cholesterol, and low-density lipoprotein cholesterol levels as compared to the HFD group. We also observed that hepatic steatosis was increased in the HFD group and was suppressed by auranofin treatment. In addition, auranofin suppressed the expressions of interleukin (IL)-1β, IL-18, caspase-1, and the NOD-like receptor family pyrin domain containing 3 (NLRP3) in the liver tissue. Furthermore, the expression of NADPH oxidase 4 and peroxisome proliferator-activated receptor γ (PPARγ), which are a major source of oxidative stress and a regulator of adipogenesis, respectively, were also decreased by auranofin. In addition, primary mouse hepatocytes were incubated with lipopolysaccharide (LPS) and palmitic acid (PA) to induce lipid accumulation and hepatic inflammation for an in vitro model. Auranofin could significantly inhibit LPS- and PA-induced inflammatory activity including nitric oxide and NLRP3 inflammasome-mediated cytokines. The results of this study demonstrate that auranofin treatment inhibits the characteristics of NAFLD through the inhibition of NLRP3 inflammasome. Therefore, auranofin may have potential as a candidate for improving NAFLD symptoms.

Download Full-text

CHANGES IN ADIPOCYTOKINES IN PATIENTS WITH ALCOHOLIC CIRRHOSIS OF THE LIVER ASSOCIATED WITH NON-ALCOHOLIC FATTY LIVER DISEASE DEPENDING ON THE STAGE OF DECOMPENSATION*

PROBLEMS OF ENDOCRINE PATHOLOGY ◽

10.21856/j-pep.2019.4.10 ◽

2019 ◽

Vol 70 (4) ◽

pp. 75-80

Author(s):

N. R. Matkovska ◽

N. H. Virstiuk ◽

U. V. Balan

Keyword(s):

Liver Cirrhosis ◽

Liver Disease ◽

Liver Function ◽

Fatty Liver ◽

Fatty Liver Disease ◽

Meld Score ◽

Lipid Metabolism Disorder ◽

Alcoholic Fatty Liver ◽

Hepatic Diseases ◽

Alcoholic Fatty Liver Disease

According to the literature, alcoholic liver disease (ALD) and non-alcoholic fatty liver disease (NAFLD) aretwo hepatic diseases with similar pathogenetic mechanisms of the development, progression and histologicalcharacteristics. Both ALD and NAFLD are associated with a lipid metabolism disorder and a disorder of thesynthesis of adipokines. Adiponectin, leptin and resistin are the most described adipokines whose role in thedevelopment and progression of diseases accompanied by lipid disorders is ambiguous and is still the subjectof scientific research. The purpose of the research was to study the changes in adipocytokines in patients withalcoholic liver cirrhosis (ALC) associated with NAFLD depending on the stage of decompensation. The study included 204 patients. Among them, 78 patients (Gr. I) had ALC and 126 patients (Gr. II) had a combination of ALCwith NAFLD. Patients were subgrouped according to compensation classes by the Child-Pugh score (A, B, C).With the progression of the liver cirrhosis the level of leptin decreased, while the levels of adiponectin andresistin increased. The higher content of leptin in patients of classes A and B is accompanied not only by theimpaired liver function, but also by its increased release from adipose tissue. In patients of class C fat depot isexhausted, therefore the level of leptin decreases. Moreover, this decrease correlates with the severity of thedisease and the prognostic MELD score. The level of adiponectin was lowered in class A patients and increasedin patients with more severe course and correlated with severity of the disease and MELD score. The level ofresistin was increased in proportion to the deterioration of the liver function and correlated with the Child-Pughscore and the MELD score. The revealed correlation between the levels of resistin, leptin and adiponectin withthe degree of severity of the liver cirrhosis and the prognostic MELD score allows considering their changes forassessment of the severity of the liver cirrhosis and predicting the course of the disease.

Download Full-text

MST1 Regulates Hepatocellular Lipophagy in Nonalcoholic Fatty Liver Disease

10.21203/rs.3.rs-783041/v1 ◽

2021 ◽

Author(s):

Wang Li ◽

Li Jia ◽

Yuhan Li ◽

Jianning Li ◽

Hui Song ◽

...

Keyword(s):

Liver Disease ◽

Mouse Model ◽

Fatty Liver ◽

Fatty Liver Disease ◽

Function Analysis ◽

Protein Markers ◽

Loss Of Function ◽

Alcoholic Fatty Liver ◽

The Impact

Abstract Background and Aims: Mammalia sterile 20-like kinase 1 (MST1) has recently been identified as an important regulator for the development of non-alcoholic fatty liver disease (NAFLD). However, the molecular mechanism of MST1 functions remains elusive. The current study is aiming to elucidate the impact and potential mechanism of MST1 in the disease progression of NAFLD. MethodsThe correlation of MST1 expression with NAFLD was determined in liver biopsy samples obtained from NAFLD patients by western blotting and IHC. The gain and loss of function analysis of MST1 was evaluated by the utilization of adenovirus or lentivirus mediated gene transfer. The impact of MST1 in lipophagy was examined by tracking the target protein markers through confocal microscopy and electron microscopy. Interaction of MST1 with the signaling molecule AMPKα/mTOR/ULK1 was evaluated by immune-blotting, in vitro kinase analysis and phosphorylation assays.Results: MST1 expression was inversely correlated with the hepatocellular lipid accumulation in both NAFLD patients and a mouse model. Impaired lipophagy was observed in the liver of Mst1-/- mice on a high fat diet. Restoration of MST1 promoted lipophagy and lipolysis in hepatocytes and the NAFLD mouse model. Further mechanistic approaches revealed that MST1 functioned to re-establish the dysfunctional autophagy/lipophagy pathway through targeting the AMPKα/mTOR/ULK1 interplay network. MST1 directly or indirectly activated ULK1 through coordination of AMPKα and mTOR/Raptor signaling pathways. Conclusions: MST1 may modulate hepatic lipid metabolism through restoration of dysfunctional autophagy and lipophagy, and thus might serve as an important therapeutic target for NAFLD.

Download Full-text

Decreased Hepatic Lactotransferrin Induces Hepatic Steatosis in Chronic Non-Alcoholic Fatty Liver Disease Model

Cellular Physiology and Biochemistry ◽

10.1159/000491535 ◽

2018 ◽

Vol 47 (6) ◽

pp. 2233-2249 ◽

Cited By ~ 4

Author(s):

Sungmin Lee ◽

Beomseok Son ◽

Jaewan Jeon ◽

Gaeul Park ◽

Hyunwoo Kim ◽

...

Keyword(s):

Liver Disease ◽

Mouse Model ◽

Fatty Liver ◽

Hepatic Steatosis ◽

Fatty Liver Disease ◽

Dietary Lipids ◽

Whole Body ◽

Alcoholic Fatty Liver ◽

Hepatic Diseases ◽

Alcoholic Fatty Liver Disease

Background/Aims: Non-alcoholic fatty liver disease (NAFLD) is an emerging metabolic disease. Although it leads to severe hepatic diseases including steatohepatitis, cirrhosis, and hepatic cancer, little is known about therapy to prevent and cure hepatic steatosis, the first step of NAFLD. We conducted this investigation to unveil the mechanism of hepatic steatosis. Methods: We established a novel chronic NAFLD mouse model through whole body irradiation and verified the model through histological and biochemical analysis. To find molecular mechanism for hepatic steatosis, we analyzed hepatic transcriptomic profiles in this model and selected target molecule. To induce the expression of lactotransferrin (Ltf) and regulate the NAFLD, growth hormone (GH) and coumestrol was introduced to hepatocyte and mice. The universal effect of coumestrol was confirmed by administration of coumestrol to NAFLD mouse model induced by high-fructose, high-fat, and MCD diet. Results: It was observed that decreased hepatic Ltf expression led to excessive hepatic lipid accumulation in NAFLD mouse. Furthermore, we found that GH was decreased in irradiated mice and functioned as an upstream regulator of Ltf expression. It was observed that GH could stimulate Ltf expression and prevent uptake of dietary lipids in hepatocytes, leading to rescue of NAFLD. Finally, we suggested that coumestrol, a kind of isoflavonoid, could be used as an inducer of hepatic Ltf expression through cooperation with the GH signaling pathway both in vitro and in vivo. Conclusions: Hepatic Ltf prevents hepatic steatosis through inhibition of dietary lipid uptake in radiation-induced NAFLD mouse model. We also suggest coumestrol as a drug candidate for prevention of NAFLD.

Download Full-text

Vitamin D levels are not associated with non-alcoholic fatty liver disease severity in a Brazilian population

International Journal for Vitamin and Nutrition Research ◽

10.1024/0300-9831/a000667 ◽

2020 ◽

pp. 1-8

Author(s):

Jeniffer Danielle M. Dutra ◽

Quelson Coelho Lisboa ◽

Silvia Marinho Ferolla ◽

Carolina Martinelli M. L. Carvalho ◽

Camila Costa M. Mendes ◽

...

Keyword(s):

Vitamin D ◽

Liver Disease ◽

Fatty Liver ◽

Disease Severity ◽

Fatty Liver Disease ◽

Hypovitaminosis D ◽

Alcoholic Fatty Liver ◽

Vitamin D Levels ◽

The Mean ◽

Alcoholic Fatty Liver Disease

Abstract. Some epidemiological evidence suggests an inverse correlation between non-alcoholic fatty liver disease (NAFLD) frequency and vitamin D levels. Likewise, a beneficial effect of vitamin D on diabetes mellitus (DM) and insulin resistance has been observed, but this is an unsolved issue. Thus, we aimed to investigate the prevalence of hypovitaminosis D in a NAFLD Brazilian population and its association with disease severity and presence of comorbidities. In a cross-sectional study, the clinical, biochemical and histological parameters of 139 NAFLD patients were evaluated according to two different cut-off points of serum 25-hydroxyvitamin D levels (20 ng/mL and 30 ng/mL). The mean age of the population was 56 ± 16 years, most patients were female (83%), 72% had hypertension, 88% dyslipidemia, 46% DM, 98% central obesity, and 82% metabolic syndrome. Serum vitamin D levels were < 30 ng/mL in 78% of the patients, and < 20 ng/mL in 35%. The mean vitamin D level was 24.3 ± 6.8 ng/mL. The comparison between the clinical, biochemical and histological characteristics of the patients according to the levels of vitamin D showed no significant difference. Most patients with NAFLD had hypovitaminosis D, but low vitamin D levels were not related to disease severity and the presence of comorbidities.

Download Full-text

Non-Alcoholic Fatty Liver Disease in Overweight Children and its Relationship with Retinol Serum Levels

International Journal for Vitamin and Nutrition Research ◽

10.1024/0300-9831.78.1.27 ◽

2008 ◽

Vol 78 (1) ◽

pp. 27-32 ◽

Cited By ~ 15

Author(s):

Suano de Souza ◽

Silverio Amancio ◽

Saccardo Sarni ◽

Sacchi Pitta ◽

Fernandes ◽

...

Keyword(s):

Insulin Resistance ◽

Liver Disease ◽

Fatty Liver ◽

Lipid Profile ◽

Fatty Liver Disease ◽

Thiobarbituric Acid ◽

Serum Levels ◽

Control Group ◽

Alcoholic Fatty Liver ◽

Alcoholic Fatty Liver Disease

Objectives: To evaluate the frequency of non-alcoholic fatty liver disease, the retinol serum levels, lipid profile, and insulin resistance in overweight/obese children. To relate these biochemical variables with the risk of this disease in the population studied. Methods: The study was cross-sectional and prospective, with 46 overweight/obese school children (28 female, 18 male; mean age 8.6 years). The control group consisted of 45 children, paired by age and gender. Hepatic steatosis, evaluated by ultrasound, was classified as normal, mild, moderate, or severe. Also evaluated were serum retinol levels; thiobarbituric acid reactive substances; lipid profile; and fasting glucose and serum insulin levels, used for the calculation of the Homeostasis Model Assessment. Results: Hepatic ultrasound alterations were found in 56.5% and 48,9% of the overweight/obese and control group children, respectively. Presence of obesity was associated with high levels of triglycerides (OR = 4.6; P = 0.002). In the studied children, the risk of steatosis was related to a trend to a higher percentage of retinol inadequacy (OR = 2.8; p = 0.051); there was no association with thiobarbituric acid reactive substances, lipid profile, or insulin resistance. Conclusions: The high frequency of non-alcoholic fatty liver disease in both groups, evaluated by hepatic ultrasound, in low-socioeconomic level children, independent of nutritional condition and without significant association with insulin resistance, emphasizes that especially in developing countries, other risk factors such as micronutrient deficiencies (e.g. vitamin A) are involved.

Download Full-text