What is Non‐Alcoholic Fatty Liver Disease (NAFLD), and Why is it Important?

Farrell, Geoffrey C.; McCullough, Arthur J.; Day, Christopher P.

doi:10.1002/9781118556153.ch1

Cited by 6 publications

(11 citation statements)

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“…Both in vitro and cultured cell studies have shown that SCP-x is the only known peroxisomal 3-keto-thiolase enzyme capable of oxidizing cholesterol’s branched side chain to form bile acids in the liver [28–30], sex steroids in the gonads [67], and steroid hormones in the adrenals [31;68]. Studies reporting a higher incidence of non-alcoholic fatty liver disease (NAFLD) and higher hepatic triglyceride accumulation in males than females, an increasing rate of NAFLD in postmenopausal women, and severe hepatic steatosis in mice ablated in aromatase suggest that NAFLD may be estrogen-associated [69–73]. Further, high-density lipoprotein-2 (HDL2) particles from females are larger and more capable of mediating cholesterol efflux from peripheral tissues [74;75].…”

Section: Discussionmentioning

confidence: 99%

Relative contributions of L-FABP, SCP-2/SCP-x, or both to hepatic biliary phenotype of female mice

Martin

Landrock

et al. 2015

Archives of Biochemistry and Biophysics

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Both sterol carrier protein-2/sterol carrier protein-x (SCP-2/SCP-x) and liver fatty acid binding protein (L-FABP) have been proposed to function in hepatobiliary bile acid metabolism/accumulation. To begin to address this issue, the impact of ablating L-FABP (LKO) or SCP-2/SCP-x (DKO) individually or both together (TKO) was examined in female mice. Biliary bile acid levels were decreased in LKO, DKO, and TKO mice; however, hepatic bile acid concentration was decreased in LKO mice only. In contrast, biliary phospholipid level was decreased only in TKO mice, while biliary cholesterol levels were unaltered regardless of phenotype. The loss of either or both genes increased hepatic expression of the major bile acid synthetic enzymes (CYP7A1 and/or CYP27A1). Loss of L-FABP and/or SCP-2/SCP-x genes significantly altered the molecular composition of biliary bile acids, but not the proportion of conjugated/unconjugated bile acids or overall bile acid hydrophobicity index. These data suggested that L-FABP was more important in hepatic retention of bile acids, while SCP-2/SCP-x more broadly affected biliary bile acid and phospholipid levels.

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Section: Discussionmentioning

confidence: 99%

Relative contributions of L-FABP, SCP-2/SCP-x, or both to hepatic biliary phenotype of female mice

Martin

Landrock

et al. 2015

Archives of Biochemistry and Biophysics

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“…Non-alcoholic fatt y liver disease (NAFLD) increases standardised mortality from cardiovascular events, common cancers, cirrhosis and hepatocellular carcinoma [1,2]. Adverse liver outcomes are confined to the 10–25% of NAFLD patients with liver fibrosis, particularly with the pathology of steatohepatitis (NASH) [3,4].…”

Section: Introductionmentioning

confidence: 99%

“…Adverse liver outcomes are confined to the 10–25% of NAFLD patients with liver fibrosis, particularly with the pathology of steatohepatitis (NASH) [3,4]. NASH occurs when overnutrition is complicated by insulin resistance and metabolic syndrome [2,5,6], particularly with a personal or family history of type 2 diabetes. Despite these connections, detailed mechanisms linking metabolic obesity to liver pathology are unclear.…”

Section: Introductionmentioning

confidence: 99%

NLRP3 inflammasome blockade reduces liver inflammation and fibrosis in experimental NASH in mice

Mridha

Wree

Robertson

et al. 2017

Journal of Hepatology

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Background & Aims: NOD-like receptor protein 3 (NLRP3) inflammasome activation occurs in Non-alcoholic fatty liver disease (NAFLD). We used the first small molecule NLRP3 inhibitor, MCC950, to test whether inflammasome blockade alters inflammatory recruitment and liver fibrosis in two murine models of steatohepatitis. Methods: We fed foz/foz and wild-type mice an atherogenic diet for 16 weeks, gavaged MCC950 or vehicle until 24 weeks, then determined NAFLD phenotype. In mice fed an methionine/choline deficient (MCD) diet, we gavaged MCC950 or vehicle for 6 weeks and determined the effects on liver fibrosis. Results: In vehicle-treated foz/foz mice, hepatic expression of NLRP3, pro-IL-1β, active caspase-1 and IL-1β increased at 24 weeks, in association with cholesterol crystal formation and NASH pathology; plasma IL-1β, IL-6, MCP-1, ALT/AST all increased. MCC950 treatment normalized hepatic caspase 1 and IL-1β expression, plasma IL-1β, MCP-1 and IL-6, lowered ALT/AST, and reduced the severity of liver inflammation including designation as NASH pathology, and liver fibrosis. In vitro, cholesterol crystals activated Kupffer cells and macrophages to release IL-1β; MCC950 abolished this, and the associated neutrophil migration. MCD diet-fed mice developed fibrotic steatohepatitis; MCC950 suppressed the increase in hepatic caspase 1 and IL-1β, lowered numbers of macrophages and neutrophils in the liver, and improved liver fibrosis. Conclusion: MCC950, an NLRP3 selective inhibitor, improved NAFLD pathology and fibrosis in obese diabetic mice. This is potentially attributable to the blockade of cholesterol crystal-mediated NLRP3 activation in myeloid cells. MCC950 reduced liver fibrosis in MCD-fed mice. Targeting NLRP3 is a logical direction in pharmacotherapy of NASH. Lay summary: Fatty liver disease caused by being overweight with diabetes and a high risk of heart attack, termed non-alcoholic steatohepatitis (NASH), is the most common serious liver disease with no current treatment. There could be several causes of inflammation in NASH, but activation of a protein scaffold within cells termed the inflammasome (NLRP3) has been suggested to play a role. Here we show that cholesterol crystals could be one pathway to activate the inflammasome in NASH. We used a drug called MCC950, which has already been shown to block NLRP3 activation, in an attempt to reduce liver injury in NASH. This drug partly reversed liver inflammation, particularly in obese diabetic mice that most closely resembles the human context of NASH. In addition, such dampening of liver inflammation in NASH achieved with MCC950 partly reversed liver scarring, the process that links NASH to the development of cirrhosis.

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“…Men have more prevalence of this disorder than women. Almost 90% of patients with non-alcoholic fatty liver are obesity (Chowdury and Younossi, 2016;Farrell et al, 2013).…”

Section: Mild Fatty Liver N %mentioning

confidence: 99%

“…The prevalence of NAFLD increases when childhood ranging from 1% in children aged 2-4 years up to 13-17% in their late teens (Adams, 2013). NAFLD has a higher prevalence in males than females (Chowdhury and Younossi, 2016;Farrell et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

USG Liver examination of Tahfiz Quran Primary School students in Berastagi

Daulay

Tala

2019

ABDIMAS

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The Liver is the largest solid organ in the human body and has many roles in maintaining a healthy body. Non-alcoholic Fatty Liver Disease (NAFLD) is a fatty liver without being accompanied by the consumption of alcohol. NAFLD is a condition that is often found in children. The majority of patients with NAFLD are asymptomatic. The diagnosis of NAFLD is usually made through imaging the liver or abnormal liver function with the presence of metabolic syndrome and or overweight. Ultrasound has high sensitivity and specificity in diagnosing NAFLD into an imaging technique that is widely used in cases with fatty liver. This community service is done to find out about the liver health of Tahfiz Quran Primary School students in Berastagi. It is also an effort to screening and early detection of liver health problems in those students. It also aims to raise awareness of heart health among students, teachers, and parents. Ultrasound liver examination of the 59 Tahfiz Quran Primary School students. Educational activities also done to educate the students about liver health. Out of 59 students, 10 students (16.9%) had mild fatty liver, 1 student (1.7%) had a calcified liver, and 36 students (61.0%) had ascites. Fatty liver was found among the students also the majority of the students had ascites.

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What is Non‐Alcoholic Fatty Liver Disease (NAFLD), and Why is it Important?

Cited by 6 publications

References 100 publications

Relative contributions of L-FABP, SCP-2/SCP-x, or both to hepatic biliary phenotype of female mice

Relative contributions of L-FABP, SCP-2/SCP-x, or both to hepatic biliary phenotype of female mice

NLRP3 inflammasome blockade reduces liver inflammation and fibrosis in experimental NASH in mice

USG Liver examination of Tahfiz Quran Primary School students in Berastagi

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