17‐Beta Hydroxysteroid Dehydrogenase 13 Deficiency Does Not Protect Mice From Obesogenic Diet Injury

Ma, Yanling; Brown, Philip M.; Lin, Dennis D.; Ma, Jing; Feng, Dechun; Belyaeva, Olga V.; Podszun, Maren C.; Roszik, Jason; Allen, Joselyn N.; Umarova, Regina; Kleiner, David E.; Kedishvili, Natalia Y.; Гаврилова, Оксана; Gao, Bin; Rotman, Yaron

doi:10.1002/hep.31517

Cited by 44 publications

(46 citation statements)

References 48 publications

(95 reference statements)

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“…A loss-of-function polymorphism in HSD17B13 was associated with less severe fatty liver disease 59 yet Hsd17b13 −/− mice were not protected from obesogenic or alcoholic liver injury. 60 These observations illustrate the need for human models to unravel mechanisms that drive advanced NAFLD.…”

Section: Discussionmentioning

confidence: 99%

Human hepatocyte PNPLA3 148M exacerbates rapid non-alcoholic steatohepatitis development in chimeric mice

Kabbani

Michailidis

Steensels

et al. 2020

Preprint

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Advanced non-alcoholic fatty liver disease (NAFLD) is a rapidly emerging global health problem associated with pre-disposing genetic polymorphisms, most strikingly an isoleucine to methionine substitution in patatin-like phospholipase domain-containing protein 3 (PNPLA3-I148M). Here, we study how human hepatocytes with PNPLA3 148I and 148M variants engrafted in the livers of chimeric mice respond to a hypercaloric Western-style diet. As early as 4 weeks, mice developed dyslipidemia, impaired glucose tolerance, and steatohepatitis selectively in the human graft, followed by pericellular fibrosis after 8 weeks of hypercaloric feeding. The PNPLA3 148M variant, either from a homozygous 148M human donor or overexpressed in a homozygous 148I donor background, caused widespread microvesicular steatosis and even more severe steatohepatitis. We conclude that PNPLA3 148M in human hepatocytes exacerbates NAFLD. These models will facilitate mechanistic studies into human genetic variants associated with advanced fatty liver diseases.

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Section: Discussionmentioning

confidence: 99%

Human hepatocyte PNPLA3 148M exacerbates rapid non-alcoholic steatohepatitis development in chimeric mice

Kabbani

Michailidis

Steensels

et al. 2020

Preprint

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“…344 Importantly, the variants that lead to loss of enzymatic function are genetically associated with improved outcomes. Although the protective phenotype could not be replicated in a mouse knockout model, 347 several pharmaceutical companies have announced the development of an HSD17B13targeted ASO, and at least one phase I clinical trial has been initiated.…”

Section: Microbial Dysbiosis and Intestinal Barrier Functionmentioning

confidence: 99%

Immunological mechanisms and therapeutic targets of fatty liver diseases

et al. 2020

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Alcoholic liver disease (ALD) and nonalcoholic fatty liver disease (NAFLD) are the two major types of chronic liver disease worldwide. Inflammatory processes play key roles in the pathogeneses of fatty liver diseases, and continuous inflammation promotes the progression of alcoholic steatohepatitis (ASH) and nonalcoholic steatohepatitis (NASH). Although both ALD and NAFLD are closely related to inflammation, their respective developmental mechanisms differ to some extent. Here, we review the roles of multiple immunological mechanisms and therapeutic targets related to the inflammation associated with fatty liver diseases and the differences in the progression of ASH and NASH. Multiple cell types in the liver, including macrophages, neutrophils, other immune cell types and hepatocytes, are involved in fatty liver disease inflammation. In addition, microRNAs (miRNAs), extracellular vesicles (EVs), and complement also contribute to the inflammatory process, as does intertissue crosstalk between the liver and the intestine, adipose tissue, and the nervous system. We point out that inflammation also plays important roles in promoting liver repair and controlling bacterial infections. Understanding the complex regulatory process of disrupted homeostasis during the development of fatty liver diseases may lead to the development of improved targeted therapeutic intervention strategies.

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“…HSD17B13 gene encodes a LD-associated protein, which is involved in regulating lipogenesis (110). Recently, the Rotman group published interesting studies on the inactivation of Hsd17b13 in mice (111) and the identification of an enzymatic active site metabolizing retinol (112).…”

Section: Hsd17b13mentioning

confidence: 99%

New Perspectives on Genetic Prediction for Pediatric Metabolic Associated Fatty Liver Disease

Lin

2020

Front. Pediatr.

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Non-alcoholic or recently re-defined metabolic associated fatty liver disease (MAFLD), a spectrum of progressive hepatic disease, has become a public health issue in obese children and adolescents. MAFLD is a complex metabolic disease strongly associated with obesity and insulin resistance. It is not known why not every obese subject will develop MAFLD. Different ethnic/racial groups display differences in MAFLD prevalence, indicating genetic factor plays a role. In the past two decades, sequence variations in genetic loci, including PNPLA3, TM6SF2, GCKR, MBOAT7, HSD17B13, etc. have been shown to confer susceptibility to MAFLD in children and adults. This review article provides an updated viewpoint of genetic predictors related to pediatric MAFLD. We discuss whether these susceptible genes can be clinically used for risk stratification and personalized care. Understanding human genetics and molecular mechanisms can give important information not only for prediction of risk but also on how to design drugs. In view of current epidemic of MAFLD worldwide, it is necessary to identify which children with MAFLD progress rapidly and need earlier intervention. In the future, a comprehensive analysis of individualized genetic and environmental factors may help assess the risk of children with MAFLD and personalize their treatment.

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17‐Beta Hydroxysteroid Dehydrogenase 13 Deficiency Does Not Protect Mice From Obesogenic Diet Injury

Cited by 44 publications

References 48 publications

Human hepatocyte PNPLA3 148M exacerbates rapid non-alcoholic steatohepatitis development in chimeric mice

Human hepatocyte PNPLA3 148M exacerbates rapid non-alcoholic steatohepatitis development in chimeric mice

Immunological mechanisms and therapeutic targets of fatty liver diseases

New Perspectives on Genetic Prediction for Pediatric Metabolic Associated Fatty Liver Disease

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