The potential role of vascular alterations and subsequent impaired liver blood flow and hepatic hypoxia in the pathophysiology of non-alcoholic steatohepatitis

Graaff, Denise van der; Kwanten, Wilhelmus J.; Francque, Sven

doi:10.1016/j.mehy.2018.11.014

Cited by 26 publications

(26 citation statements)

References 137 publications

(163 reference statements)

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“…Notably, the ACC inhibitor GS-0976 is currently under investigation in clinical trials for the treatment of NASH (NCT02856555). Similarly, hypoxia-inducible factor 1α (HIF-1α), a transcription factor that induces glycolysis and a known regulator of differentiation toward a Th17 phenotype at the expense of the Treg cell subset, is an upcoming player in obesity-associated chronic inflammation and NAFLD (170–174).…”

Section: Interplay Between Adipose Tissue Liver and Gutmentioning

confidence: 99%

The Differential Roles of T Cells in Non-alcoholic Fatty Liver Disease and Obesity

et al. 2019

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Non-alcoholic fatty liver disease (NAFLD) constitutes a spectrum of disease states characterized by hepatic steatosis and is closely associated to obesity and the metabolic syndrome. In non-alcoholic steatohepatitis (NASH), additionally, inflammatory changes and hepatocellular damage are present, representing a more severe condition, for which the treatment is an unmet medical need. Pathophysiologically, the immune system is one of the main drivers of NAFLD progression and other obesity-related comorbidities, and both the innate and adaptive immune system are involved. T cells form the cellular component of the adaptive immune system and consist of multiple differentially active subsets, i.e., T helper (Th) cells, regulatory T (Treg) cells, and cytotoxic T (Tc) cells, as well as several innate T-cell subsets. This review focuses on the role of these T-cell subsets in the pathogenesis of NAFLD, as well as the association with obesity and type 2 diabetes mellitus, reviewing the available evidence from both animal and human studies. Briefly, Th1, Th2, Th17, and Th22 cells seem to have an attenuating effect on adiposity. Th2, Th22, and Treg cells seem to decrease insulin resistance, whereas Th1, Th17, and Tc cells have an aggravating effect. Concerning NAFLD, both Th22 and Treg cells appear to have an overall tempering effect, whereas Th17 and Tc cells seem to induce more liver damage and fibrosis progression. The evidence regarding the role of the innate T-cell subsets is more controversial and warrants further exploration.

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Section: Interplay Between Adipose Tissue Liver and Gutmentioning

confidence: 99%

The Differential Roles of T Cells in Non-alcoholic Fatty Liver Disease and Obesity

et al. 2019

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“…Hepatic LTX produces OS, which activates Kupffer cells (KC) and hepatic stellate cells (HSC), inducing fibrosis in hepatic tissue [ 48 ]. OS-induced KC activation triggers an innate and adaptive immune response with the release of proinflammatory cytokines and chemokines, which activate natural killer T cells and HSC [ 48 , 49 ]. This response is reinforced by OS generated in hepatocytes.…”

Section: Influence Of Oxidative Stress In Nonalcoholic Fatty Livermentioning

confidence: 99%

“…A consequence of the decreased NO is the decline in vasodilation response and liver circulation and the decrease in its anti-inflammatory, antithrombotic, antifibrogenic, and antioxidant properties in the endothelium [ 51 ]. Besides, hypoxia observed from damage in the pericentral region of the liver lobule and around the portal vein could induce OS-dependent hepatic angiogenesis and vascular growth, leading to ED [ 49 ].…”

Section: Influence Of Oxidative Stress In Nonalcoholic Fatty Livermentioning

confidence: 99%

Role of Oxidative Stress in Hepatic and Extrahepatic Dysfunctions during Nonalcoholic Fatty Liver Disease (NAFLD)

González

Huerta-Salgado

Orozco-Aguilar

et al. 2020

Oxidative Medicine and Cellular Longevity

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Nonalcoholic fatty liver disease (NAFLD) is a pathology that contains a broad liver dysfunctions spectrum. These alterations span from noninflammatory isolated steatosis until nonalcoholic steatohepatitis (NASH), a more aggressive form of the disease characterized by steatosis, inflammatory status, and varying liver degrees fibrosis. NAFLD is the most prevalent chronic liver disease worldwide. The causes of NAFLD are diverse and include genetic and environmental factors. The presence of NASH is strongly associated with cirrhosis development and hepatocellular carcinoma, two conditions that require liver transplantation. The liver alterations during NAFLD are well described. Interestingly, this pathological condition also affects other critical tissues and organs, such as skeletal muscle and even the cardiovascular, renal, and nervous systems. Oxidative stress (OS) is a harmful state present in several chronic diseases, such as NAFLD. The purpose of this review is to describe hepatic and extrahepatic dysfunctions in NAFLD. We will also review the influence of OS on the physiopathological events that affect the critical function of the liver and peripheral tissues.

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“…This hypothesis is supported by studies in animal models [52][53][54] and in humans, 55 showing an early increase in intrahepatic vascular resistance to portal blood flow during the development of disease. These effects on liver microcirculation seem to be mediated by fat accumulation, insulin resistance, sinusoidal endothelial dysfunction, 52,53,56 increased thromboxane and liver endothelin-1 expression, 53 parenchymal hypoxia, 54,56 and architectural derangement of sinusoidal anatomy. 53 In a study exploring portal pressure in individuals with NAFLD undergoing transjugular liver biopsy, the degree of steatosis was the unique factor independently predicting the presence of portal hypertension.…”

Section: Role Of Age Gender and Body Sizementioning

confidence: 80%

(13C)-Methacetin breath test provides evidence of subclinical liver dysfunction linked to fat storage but not lifestyle

et al. 2021

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Background & Aims Non-alcoholic fatty liver disease (NAFLD) is characterised by the presence of hepatic steatosis in the absence of other causes of secondary hepatic fat accumulation, and is usually associated with visceral, metabolically active obesity. However, the subclinical effects of body and liver fat accumulation on liver function are still unclear. Methods We used orally administered ( 13 C)-methacetin and breath test to quantify the efficiency of hepatic extraction from portal blood flow and liver microsomal function in 81 participants, in relation to presence/absence of ultrasonographic NAFLD, extent of body fat accumulation, insulin resistance, dietary models, and lifestyle. Results NAFLD was present in 23% of participants with normal weight, and prevalence increased with body fat and insulin resistance. Fat accumulation, NAFLD, and insulin resistance were associated with decreased hepatic extraction efficiency, and liver microsomal function was impaired in moderate-to-severe NAFLD. Caloric intake, dietary models, and lifestyles had a minor role in promoting functional changes. Conclusions The interplay between body fat accumulation, insulin resistance, and NAFLD is linked with altered hepatic extraction efficiency from blood flow and deranged microsomal function. Non-invasive diagnosis of subclinical alterations of liver function is relevant for primary and secondary prevention measures. Furthermore, the occurrence of NAFLD in lean individuals and the evidence that caloric intake, dietary models, and lifestyle played a minor role require further studies exploring the role of environmental factors in the natural history of these diseases. Lay summary Obesity is progressively increasing worldwide and is paralleled by fat accumulation in the liver (non-alcoholic fatty liver disease [NAFLD]), the most common chronic liver disease worldwide. NAFLD can alter liver structure and function, with a variety of consequences ranging from asymptomatic and subclinical alterations to cirrhosis and cancer. ( 13 C)-Methacetin breath test, a non-invasive diagnostic tool, can reveal early subclinical alterations of liver dynamic function in individuals with obesity and in patients with NAFLD.

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The potential role of vascular alterations and subsequent impaired liver blood flow and hepatic hypoxia in the pathophysiology of non-alcoholic steatohepatitis

Cited by 26 publications

References 137 publications

The Differential Roles of T Cells in Non-alcoholic Fatty Liver Disease and Obesity

The Differential Roles of T Cells in Non-alcoholic Fatty Liver Disease and Obesity

Role of Oxidative Stress in Hepatic and Extrahepatic Dysfunctions during Nonalcoholic Fatty Liver Disease (NAFLD)

(13C)-Methacetin breath test provides evidence of subclinical liver dysfunction linked to fat storage but not lifestyle

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