Geographical similarity and differences in the burden and genetic predisposition of NAFLD

Yip, Terry Cheuk‐Fung; Vilar‐Gomez, Eduardo; Petta, Salvatore; Yılmaz, Yusuf; Wong, Grace Lai–Hung; Adams, Leon A.; Lédinghen, Victor de; Sookoian, Silvia; Wong, Vincent Wai‐Sun

doi:10.1002/hep.32774

Cited by 61 publications

(42 citation statements)

References 218 publications

(501 reference statements)

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“…Along with nutritional factors, the role of genetic, microbial, metabolic, and other environmental factors has been investigated (16)(17)(18)(19). Several common genetic variants have been associated with NAFLD in adults and youth.…”

Section: Pathogenesis Of Nafldmentioning

confidence: 99%

Clinical features and metabolic complications for non-alcoholic fatty liver disease (NAFLD) in youth with obesity

2023

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Pediatric obesity has become in the last forty years the most common metabolic disease in children and adolescents affecting about 25% of the pediatric population in the western world. As obesity worsens, a whole-body insulin resistance (IR) occurs. This phenomenon is more pronounced during adolescence, when youth experience a high degree of insulin resistance due the production of growth hormone. As IR progresses, the blunted control of insulin on adipose tissue lipolysis causes an increased flux of fatty acids with FFA deposition in ectopic tissues and organs such as the liver, leading to the development of NAFLD. In this brief review, we will discuss the clinical implications of IR and NAFLD in the context of pediatric obesity. We will review the pathogenesis and the link between these two entities, the major pathophysiologic underpinnings, including the role of genetics and metagenomics, how these two entities lead to the development of type 2 diabetes, and which are the therapeutic options for NAFLD in youth.

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Section: Pathogenesis Of Nafldmentioning

confidence: 99%

Clinical features and metabolic complications for non-alcoholic fatty liver disease (NAFLD) in youth with obesity

2023

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“…Nonalcoholic fatty liver disease (NAFLD) affects over 30% of the general adult population and is emerging as an important cause of cirrhosis and hepatocellular carcinoma. 1 Its more active form nonalcoholic steatohepatitis (NASH) is characterized by the presence of hepatic steatosis, inflammation (both lobular and portal) and hepatocyte ballooning. Assessment of inflammation is important.…”

Section: Introductionmentioning

confidence: 99%

Non-invasive biomarkers for liver inflammation in non-alcoholic fatty liver disease: present and future

Yip¹,

Lyu²,

Lin³

et al. 2023

Clin Mol Hepatol

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Terry Yip has served as a speaker and an advisory committee member for Gilead Sciences.Vincent Wong has served as an advisory committee member for AbbVie, Allergan, Echosens, Gilead Sciences, Janssen, Perspectum Diagnostics, Pfizer and Terns, and a speaker for Bristol-Myers Squibb, Echosens, Gilead Sciences and Merck.Grace Wong has served as an advisory committee member for Gilead Sciences and Janssen, as a speaker for Abbott,

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“…In general, NAFLD is considered to be the hepatic manifestation of metabolic syndrome, which is most commonly observed in cases of obesity and/or type 2 diabetes mellitus (T2DM), and not only constitutes a first stage in this disease, but the toxicity exerted by certain lipids might also drive further steps in this disease, such as inflammation and liver injury ( 3 ). The rise in NAFLD has led to a remarkable increase in the number of cases of cirrhosis, hepatocellular carcinoma, hepatic decompensation, and liver-related mortality related to NAFLD ( 4 ). It is currently believed that chronic inflammation caused by excessive deposition of liver fat and changes in the local immune environment are important mechanisms that lead to the transformation of NAFLD to hepatocellular carcinoma (HCC) ( 5 , 6 ).…”

Section: Introductionmentioning

confidence: 99%

TSH−SPP1/TRβ−TSH positive feedback loop mediates fat deposition of hepatocyte: Crosstalk between thyroid and liver

Huang

Wen

2022

Front. Immunol.

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AimsWe conducted this study with two aims: (1) whether TRβ could be damaged by NAFLD, thereby represent thyroid hormone resistance-like manifestation and (2) to analyze the potential role of SPP1 in TH signaling pathway on the process of NAFLD. This study is expected to provide a new perspective on the therapeutic mechanism in the pathological course of NAFLD.MethodsA total of 166 patients diagnosed with type 2 diabetes mellitus (T2DM) were enrolled in this study. All patients had a BMI above 24 kg/m2 and were stratified into two groups: NAFLD and Non-NAFLD groups. Ages, gender, BMI, duration of diabetes and biochemical markers were obtained from participants’ records. We downloaded the dataset GSE48452 from GEO. The Pathview library was used to make the thyroid hormone signaling pathway visualization. The CIBERSORT algorithm was applied to calculate the infiltrated immune cells in obese NAFLD patients. C57BL/6 mice were randomly selected to constitute the normal control (NC) group and were fed a normal chow diet; the rest of the mice were fed a high-fat diet (HFD). After 12 weeks HFD feeding, the mice were sacrificed by cervical dislocation, and blood samples were collected. Mouse livers were also collected; one part of each liver was fixed in 10% formalin for histological analysis, and the other part was snap-frozen for subsequent molecular analyses. To explore the relationship between SPP1, TRβ and lipid deposition in hepatocytes, HepG2 cells were treated with 50 μ M concentration of PA and/or 20 ng/ml concentration of rh-SPP1 for 48h. In addition, the PC3.1-TRβ plasmid was constructed for further validation in HepG2 cells. We used THP-1 cells to construct an M1 macrophage model in vitro. We then analyzed THP-1 cells treated with various concentrations of PA or TSH.Results(1) After adjusting for all factors that appeared P value less than 0.1 in the univariate analysis, BMI, TSH, and FT3 were significant independent risk factors of NAFLD (ORs were 1.218, 1.694, and 2.259, respectively); (2) A further analysis with BMI stratification indiacted that both FT3 and TSH had a significant change between individuals with NAFLD and Non-NAFLD in obesity subgroup; however, there was no statistic difference in over-weight group; (3) Bioinformatics analysis of GSE48452 had shown that several key molecular (including TRβ) of thyroid hormone pathway affected by NAFLD induced transcriptomic changes and the expression levels of SPP1, FABP4 and RPS4Y1 were significantly higher, while the expression levels of PZP and VIL1 were significantly decreased in NAFLD patients(adjusted p < 0.05, |logFC| > 1.0). The CIBERSORT algorithm showed increased M0 and M1, decreased M2 macrophage infiltration in NAFLD with comparison to healthy obese group; (4) After 12 weeks of HFD-feeding, the obesity mice had significantly higher serum TSH and In IHC-stained liver sections of obesity group, the intensity of SPP1 had a significantly increased, while TRβ reduced; (5) In vitro studies have shown SPP1 aggravated lipid deposition in hepatic cells dependent on down-regulating the expression of TRβ and TSH acts to promote secretion of SPP1 in M1 macrophage cells.ConclusionsSPP1 secretion induced by M1 macrophage polarization, which may down-regulates TRβ in hepatocytes via paracrine manner, on the one hand, the lipid deposition aggravating in liver, on the other hand, a compensatory increase of TSH in serum. The increased TSH can further lead to the following SPP1 secretion of M1 macrophage. The positive feedback crosstalk between thyroid and liver, may be plays an important role in maintaining and amplifying pathological process of NAFLD.

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Geographical similarity and differences in the burden and genetic predisposition of NAFLD

Cited by 61 publications

References 218 publications

Clinical features and metabolic complications for non-alcoholic fatty liver disease (NAFLD) in youth with obesity

Clinical features and metabolic complications for non-alcoholic fatty liver disease (NAFLD) in youth with obesity

Non-invasive biomarkers for liver inflammation in non-alcoholic fatty liver disease: present and future

TSH−SPP1/TRβ−TSH positive feedback loop mediates fat deposition of hepatocyte: Crosstalk between thyroid and liver

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