Histopathological differences utilizing the nonalcoholic fatty liver disease activity score criteria in diabetic (type 2 diabetes mellitus) and non-diabetic patients with nonalcoholic fatty liver disease

Puchakayala, Bharat; Verma, Siddharth; Kanwar, Pushpjeet; Hart, John; Sanivarapu, Raghavendra; Mohanty, Smruti R.

doi:10.4254/wjh.v7.i25.2610

Cited by 24 publications

(14 citation statements)

References 28 publications

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“…Besides phenotypically readily apparent subtypes of NASH patients, such as lean vs. obese patients (Kumar and Mohan, 2017 ) or diabetic vs. non-diabetic patients (Puchakayala et al, 2015 ), recent efforts on subtyping NAFLD/NASH patients on the basis of their serum metabolome (Alonso et al, 2017 ; Iruarrizaga-Lejarreta et al, 2017 ) have revealed that patients may also be classified on the basis of their molecular disease patterns and have provided insight into molecular pathways that may be impaired in some but not other patients (i.e., synthesis of S-adenosylmethionine). A similar analysis in the Ldlr −/− .Leiden mouse revealed that on the metabolome level this model reflects a substantial proportion of NAFLD/NASH patients (Morrison et al, 2017 ) but the underlying disease mechanisms remain unclear.…”

Section: Discussionmentioning

confidence: 99%

Key Inflammatory Processes in Human NASH Are Reflected in Ldlr−/−.Leiden Mice: A Translational Gene Profiling Study

et al. 2018

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Introduction: It is generally accepted that metabolic inflammation in the liver is an important driver of disease progression in NASH and associated matrix remodeling/fibrosis. However, the exact molecular inflammatory mechanisms are poorly defined in human studies. Investigation of key pathogenic mechanisms requires the use of pre-clinical models, for instance for time-resolved studies. Such models must reflect molecular disease processes of importance in patients. Herein we characterized inflammation in NASH patients on the molecular level by transcriptomics and investigated whether key human disease pathways can be recapitulated experimentally in Ldlr−/−.Leiden mice, an established pre-clinical model of NASH.Methods: Human molecular inflammatory processes were defined using a publicly available NASH gene expression profiling dataset (GSE48452) allowing the comparison of biopsy-confirmed NASH patients with normal controls. Gene profiling data from high-fat diet (HFD)-fed Ldlr−/−.Leiden mice (GSE109345) were used for assessment of the translational value of these mice.Results: In human NASH livers, we observed regulation of 65 canonical pathways of which the majority was involved in inflammation (32%), lipid metabolism (16%), and extracellular matrix/remodeling (12%). A similar distribution of pathways across these categories, inflammation (36%), lipid metabolism (24%) and extracellular matrix/remodeling (8%) was observed in HFD-fed Ldlr−/−.Leiden mice. Detailed evaluation of these pathways revealed that a substantial proportion (11 out of 13) of human NASH inflammatory pathways was recapitulated in Ldlr−/−.Leiden mice. Furthermore, the activation state of identified master regulators of inflammation (i.e., specific transcription factors, cytokines, and growth factors) in human NASH was largely reflected in Ldlr−/−.Leiden mice, further substantiating its translational value.Conclusion: Human NASH is characterized by upregulation of specific inflammatory processes (e.g., “Fcγ Receptor-mediated Phagocytosis in Macrophages and Monocytes,” “PI3K signaling in B Lymphocytes”) and master regulators (e.g., TNF, CSF2, TGFB1). The majority of these processes and regulators are modulated in the same direction in Ldlr−/−.Leiden mice fed HFD with a human-like macronutrient composition, thus demonstrating that specific experimental conditions recapitulate human disease on the molecular level of disease pathways and upstream/master regulators.

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Section: Discussionmentioning

confidence: 99%

Key Inflammatory Processes in Human NASH Are Reflected in Ldlr−/−.Leiden Mice: A Translational Gene Profiling Study

et al. 2018

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“…The association between T2DM and the more severe forms of NAFLD was also reported by Loomba et al [84] in an observational study enrolling 1,069 T2DM patients with biopsy-proven NAFLD, documenting a significant association between history of diabetes mellitus, NASH and advanced fibrosis, even after adjusting for age, sex, body mass index, ethnicity, and presence of metabolic syndrome. Moreover, in a retrospective analysis of 235 patients with biopsy-proven NAFLD with and without T2DM, Puchakayala et al [85] documented that among T2DM patients with NAFLD, the prevalence of advanced fibrosis and ballooning were significantly greater as compared to patients with NAFLD but without T2DM. Interestingly and importantly, in the multivariate regression analysis, T2DM was associated with NASH and fibrosis in all patients with NAFLD [85] .…”

Section: Prevalence Of Nafld In Patients With Diabetes Mellitusmentioning

confidence: 99%

“…Moreover, in a retrospective analysis of 235 patients with biopsy-proven NAFLD with and without T2DM, Puchakayala et al [85] documented that among T2DM patients with NAFLD, the prevalence of advanced fibrosis and ballooning were significantly greater as compared to patients with NAFLD but without T2DM. Interestingly and importantly, in the multivariate regression analysis, T2DM was associated with NASH and fibrosis in all patients with NAFLD [85] . These data were additionally replicated in a recent meta-analysis by Younossi et al [86] including 80 observational studies for a total of nearly 49,500 individuals with T2DM (mean age: 58 years; mean body mass index: 28 kg/m 2 ; percentage of men: 53%).…”

Section: Prevalence Of Nafld In Patients With Diabetes Mellitusmentioning

confidence: 99%

Prevalence and incidence of intra- and extrahepatic complications of NAFLD in patients with type 2 diabetes mellitus

Mantovani¹,

Beatrice²,

Stupia³

et al. 2020

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Nonalcoholic fatty liver disease (NAFLD) is linked to abdominal obesity, insulin resistance and type 2 diabetes mellitus (T2DM). The association of NAFLD with T2DM is bidirectional. In fact, evidence suggests that abdominal obesity, T2DM and metabolic syndrome play a part in the development and progression of NAFLD. Alternatively, NAFLD is associated with an increased risk of having T2DM and metabolic syndrome. According to this background, it is unsurprising that patients with T2DM patients also have a higher prevalence of NAFLD than those with no T2DM, as well as an increased risk of developing liver-related and extrahepatic complications, mainly cardiovascular and renal diseases. Seeing the relationship of NAFLD with insulin resistance, obesity and T2DM, recent consensus proposes a change in nomenclature from NAFLD to metabolic associated fatty liver disease. In this review, we will discuss the prevalence and incidence of NAFLD (as detected by imaging techniques or liver biopsy) in patients with type T2DM with particular regard to hepatic and extrahepatic complications.

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“…NASH can lead to fibrosis and eventually cirrhosis (Ratziu et al, 2010). Patients with type 2 diabetes and NAFLD tend to have more advanced stages of NAFLD with higher rate of ballooning and advanced fibrosis than patients with NAFLD without type 2 diabetes (Puchakayala et al, 2015). Based on imaging studies, the global prevalence of NAFLD is about 25%.…”

Section: Introductionmentioning

confidence: 99%

Cardiometabolic effects of antidiabetic drugs in non‐alcoholic fatty liver disease

Rix

Pedersen

Storgaard

et al. 2018

Clin Physio Funct Imaging

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Histopathological differences utilizing the nonalcoholic fatty liver disease activity score criteria in diabetic (type 2 diabetes mellitus) and non-diabetic patients with nonalcoholic fatty liver disease

Abstract: AIM:To study clinical and histopathological features of nonalcoholic fatty liver disease (NAFLD) in patients with and without type 2 diabetes mellitus (T2DM) using updated nonalcoholic steatohepatitis clinical research network (NASH-CRN) grading system.

Cited by 24 publications

References 28 publications

Key Inflammatory Processes in Human NASH Are Reflected in Ldlr−/−.Leiden Mice: A Translational Gene Profiling Study

Key Inflammatory Processes in Human NASH Are Reflected in Ldlr−/−.Leiden Mice: A Translational Gene Profiling Study

Prevalence and incidence of intra- and extrahepatic complications of NAFLD in patients with type 2 diabetes mellitus

Cardiometabolic effects of antidiabetic drugs in non‐alcoholic fatty liver disease

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