Pathophysiology of Nonalcoholic Fatty Liver Disease/Nonalcoholic Steatohepatitis

Manne, Vignan; Handa, Priya; Kowdley, Kris V.

doi:10.1016/j.cld.2017.08.007

Cited by 271 publications

(240 citation statements)

References 101 publications

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“…The prevalence of NAFLD is growing due to its close association with obesity, type 2 diabetes, and the metabolic syndrome . NAFLD is an umbrella term describing a continuum of liver disorders ranging from nonalcoholic fatty liver (NAFL) to nonalcoholic steatohepatitis (NASH), its progressive inflammatory form, which can predispose to cirrhosis and hepatocellular (HC) carcinoma . The pathophysiology of NASH is not fully understood, and the mechanisms resulting in the transition from NAFL to NASH are active areas of research …”

Section: Introductionmentioning

confidence: 99%

“…1 NAFLD is an umbrella term describing a continuum of liver disorders ranging from nonalcoholic fatty liver (NAFL) to nonalcoholic steatohepatitis (NASH), its progressive inflammatory form, which can predispose to cirrhosis and hepatocellular (HC) carcinoma. 2 The pathophysiology of NASH is not fully understood, and the mechanisms resulting in the transition from NAFL to NASH are active areas of research. 1,2 Abbreviations: BMDM, bone marrow-derived macrophages; HC, hepatocellular; MDM, monocyte-derived macrophages; NAFLD, nonalcoholic fatty liver disease; NASH, nonalcoholic steatohepatitis; RES, reticuloendothelial system.…”

Section: Introductionmentioning

confidence: 99%

“…2 The pathophysiology of NASH is not fully understood, and the mechanisms resulting in the transition from NAFL to NASH are active areas of research. 1,2 Abbreviations: BMDM, bone marrow-derived macrophages; HC, hepatocellular; MDM, monocyte-derived macrophages; NAFLD, nonalcoholic fatty liver disease; NASH, nonalcoholic steatohepatitis; RES, reticuloendothelial system.…”

Section: Introductionmentioning

confidence: 99%

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Iron alters macrophage polarization status and leads to steatohepatitis and fibrogenesis

Handa¹,

Thomas

Morgan-Stevenson³

et al. 2019

Journal of Leukocyte Biology

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145

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We have previously demonstrated that iron overload in hepatic reticuloendothelial system cells (RES) is associated with severe nonalcoholic steatohepatitis (NASH) and advanced fibrosis in patients with nonalcoholic fatty liver disease (NAFLD). Recruited myeloid‐derived macrophages have gained a pivotal position as drivers of NASH progression and fibrosis. In this study, we used bone marrow‐derived macrophages (BMDM) from C57Bl6 mice as surrogates for recruited macrophages and examined the effect of iron on macrophage polarization. Treatment with iron (ferric ammonium citrate, FAC) led to increased expression levels of M1 markers: CCL2, CD14, iNOS, IL‐1β, IL‐6, and TNF‐α; it also increased protein levels of CD68, TNF‐α, IL‐1β, and IL‐6 by flow cytometry. This effect could be reversed by desferrioxamine, an iron chelator. Furthermore, iron loading of macrophages in the presence of IL‐4 led to the down‐regulation of M2 markers: arginase‐1, Mgl‐1, and M2‐specific transcriptional regulator, KLF4. Iron loading of macrophages with IL‐4 also resulted in reduced phosphorylation of STAT6, another transcriptional regulator of M2 activation. Dietary iron overload of C57Bl6 mice led to hepatic macrophage M1 activation. Iron overload also stimulated hepatic fibrogenesis. Histologic analysis revealed that iron overload resulted in steatohepatitis. Furthermore, NAFLD patients with hepatic RES iron deposition had increased hepatic gene expression levels of M1 markers, IL‐6, IL‐1β, and CD40 and reduced gene expression of an M2 marker, TGM2, relative to patients with hepatocellular iron deposition pattern. We conclude that iron disrupts the balance between M1/M2 macrophage polarization and leads to macrophage‐driven inflammation and fibrogenesis in NAFLD.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Iron alters macrophage polarization status and leads to steatohepatitis and fibrogenesis

Handa¹,

Thomas

Morgan-Stevenson³

et al. 2019

Journal of Leukocyte Biology

Self Cite

145

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“…In this study, we diagnosed the NAFLD by routine blood testing and liver ultrasonography instead of biopsy, which is regarded as the gold standard of NAFLD diagnosis. In the majority of cases, patients with NAFLD possessed elevated levels of serum lipid profiles and liver enzymes, especially ALT and GGT, which had been used as the marker of liver injury (27)(28)(29). In our study, there was a significantly higher level of serum TG, TC, LDL, ALT, GGT, and ALP in NAFLD patients compared to the healthy controls.…”

Section: Discussionmentioning

confidence: 46%

Association Between Four ABCA1 gene Polymorphisms and Risk of Non-Alcoholic Fatty Liver Disease in a Chinese Han Population

Liu¹,

Lu²,

Liao

et al. 2018

Hepat Mon

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Background: Non-alcoholic fatty liver disease (NAFLD) as a severe health problem is the leading cause of morbidity and mortality from the chronic liver disease worldwide. NAFLD is tightly associated with dyslipidemia although the etiology is still unclear. ATP binding cassette subfamily A member 1 (ABCA1) is involved in cholesterol efflux, fatty acid oxidation, and inflammation. Although some reports show that the ABCA1 polymorphisms affect the lipids metabolism and severity of clinical liver diseases, the effects of ABCA1 polymorphisms on the development of NAFLD are unknown. Objectives: The current study was performed to investigate the association between the ABCA1 polymorphisms and the development of NAFLD and the effect of the four ABCA1 SNPs on the serum lipid levels. Methods: The ABCA1 polymorphisms (rs1800977, rs2066714, rs2066715, and rs2230808) were determined in 265 NAFLD patients and 126 healthy controls using the sequencing and polymerase chain reaction analysis. Serum lipid profiles and liver enzymes were examined using standard clinical laboratory methods. Results: There was a significant difference (P < 0.05) in the genotype of the ABCA1 rs1800977 G/A polymorphisms between NAFLD patients and healthy controls. No significant differences were found in genotypes and allele frequencies of the ABCA1 rs2066714T/C, rs2066715T/C, and rs2230808C/T between NAFLD patients and healthy controls. The ABCA1 rs1800977 A was independently associated with NAFLD after adjusting for the effects of age, gender, and BMI. Compared to the noncarriers in NAFLD patients, the carriers of ABCA1 rs2066714 C showed a significantly higher level of LDL (P = 0.045) and the carriers of ABCA1 rs2230808 T showed a significantly lower level of HDL (P = 0.039). Conclusions:We first demonstrated the association between the ABCA1 polymorphisms and the risk of NAFLD in a Chinese Han population. The ABCA1 rs1800977 may be a protective factor against the development of NAFLD. The ABCA1 rs2066714 C allele could increase the serum LDL cholesterol level, and the ABCA1 rs2230808 T allele could decrease the serum HDL cholesterol level in NAFLD patients.

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“…It is estimated that the incidence of NAFLD in women of childbearing age is 10% . NAFLD is considered as a hepatic manifestation of the metabolic syndrome and is an endpoint of a complex combination of adipose tissue dysfunction with increased lipolysis and insulin resistance, defects in hepatic clearance of lipids, de novo hepatic lipogenesis, and lipotoxicity with oxidative stress and mitochondrial dysfunction . In the first two thirds of pregnancy, maternal hyperphagia and increases in lipogenesis lead to increased fat stores, whereas maternal catabolism in the third trimester leads to enhanced adipose tissue lipolysis with increased levels of free fatty acids and glycerol that are metabolized and re‐esterified for the production of triglycerides, including very low‐density lipoproteins .…”

Section: Primary Liver Diseases That Are Concurrent With Pregnancymentioning

confidence: 99%

Liver Disease in Pregnancy: What's New

Brady

2020

Hepatol Commun

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Liver disease in pregnancy may present as a disorder that is unique to pregnancy or as an acute or chronic liver disease occurring coincidentally in pregnancy. Hepatic diseases that are unique to pregnancy include hyperemesis gravidarum; preeclampsia/eclampsia; the syndrome of hemolysis, elevated liver enzymes, and low platelets; intrahepatic cholestasis of pregnancy; and acute fatty liver of pregnancy. Acute and chronic forms of primary hepatic disorders that are seen in pregnancy include viral hepatitis, autoimmune hepatitis, nonalcoholic fatty liver disease, and cirrhosis. Because of the need to consider both maternal and fetal health, there are special considerations for the implementation of diagnostic strategies and pharmacologic therapies for liver disease that occurs in pregnancy. An understanding of the pathogenesis and expression of liver diseases in pregnancy has been evolving, and various diagnostic and prognostic tools have been studied in order to determine noninvasive approaches to identifying and staging of such diseases. Investigations have also been underway to evaluate the safety and utility of existing and new therapeutic agents that previously were thought to not be compatible with pregnancy. This review will explore updates in the epidemiology, diagnosis, and management of various liver diseases seen in pregnancy. (Hepatology Communications 2020;4:145-156).

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Pathophysiology of Nonalcoholic Fatty Liver Disease/Nonalcoholic Steatohepatitis

Cited by 271 publications

References 101 publications

Iron alters macrophage polarization status and leads to steatohepatitis and fibrogenesis

Iron alters macrophage polarization status and leads to steatohepatitis and fibrogenesis

Association Between Four ABCA1 gene Polymorphisms and Risk of Non-Alcoholic Fatty Liver Disease in a Chinese Han Population

Liver Disease in Pregnancy: What's New

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