Hypertension, diabetes, atherosclerosis and NASH: Cause or consequence?

Lonardo, Amedeo; Nascimbeni, Fabio; Mantovani, Alessandro; Targher, Giovanni

doi:10.1016/j.jhep.2017.09.021

Cited by 520 publications

(396 citation statements)

References 209 publications

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“…Non‐alcoholic fatty liver disease (NAFLD) has become the most prevalent chronic liver disease globally . There is a bi‐directional association between NAFLD and insulin resistance, diabetes and components of the metabolic syndrome . The most common cause of death in NAFLD is cardiovascular disease (CVD) .…”

Section: Introductionmentioning

confidence: 99%

Cardiovascular risk factors in non‐alcoholic fatty liver disease

Hagström

Nasr

Ekstedt

et al. 2018

Liver International

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Background & Aims Patients with non‐alcoholic fatty liver disease (NAFLD) are at an increased risk for cardiovascular disease (CVD). It is unclear whether histological variables may help predict CVD risk. We evaluated histology and traditional CV risk factors as predictors of CVD outcomes in a large NAFLD cohort. Methods We included 603 biopsy‐proven NAFLD patients free of baseline CVD and matched these (1:10, by age, sex and municipality) to 6269 population controls. All individuals were cross‐linked to national registries to ascertain incident CVD events, defined as acute ischaemic heart disease or stroke. The presence of CV risk factors and liver histology were available in NAFLD patients only. Cox regression models were used to estimate hazard ratios (HR) for incident CVD. Results During a mean follow‐up of 18.6 years, 168 (28%) of NAFLD patients and 1325 (21%) of controls experienced a CVD event (HR 1.54, 95%CI 1.30‐1.83). Within the NAFLD cohort, age, male sex, type 2 diabetes, smoking and triglycerides were associated with risk of CVD. Taking these CV risk factors into account, no histological parameter, including presence of NASH and fibrosis stage, were associated with incident CVD. Conclusions Patients with NAFLD are at an increased risk for CVD compared to matched controls, but histological parameters do not seem to independently predict this risk.

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Section: Introductionmentioning

confidence: 99%

Cardiovascular risk factors in non‐alcoholic fatty liver disease

Hagström

Nasr

Ekstedt

et al. 2018

Liver International

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“…Diabetes is very common and affects patients with typical macroangiopathic cardiovascular diseases, which comprise ischaemic stroke, peripheral arterial disease and myocardial infarction [1,2]. However, there are debates about the causative role of high blood glucose for cerebral small vessel disease.…”

Section: Introductionmentioning

confidence: 99%

“…Upon path-DOI: 10.1159/000494990 ological analysis, it was found that these focal areas correspond to hemosiderin deposits in the cerebral microvascular perivascular spaces [5][6][7][8]. Such cerebral small vessel diseases, such as white matter lesions (WMLs) and lacunar infarcts, occur more frequently in the elderly and are linked with high blood glucose [1][2]. If blood glucose levels are, indeed, involved in the cerebral small vessel disease, they may also be involved in CMBs.…”

Section: Introductionmentioning

confidence: 99%

Blood Glucose Levels Are Associated with Cerebral Microbleeds in Patients with Acute Ischaemic Stroke

Lei¹,

Zhong²,

Ling³

et al. 2018

Eur Neurol

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Background and Purpose: There are debates about the causative role of high blood glucose in cerebral small vessel disease. The relationship between cerebral microbleeds (CMBs) and blood glucose is unclear. Methods: Patients admitted to our department with acute ischaemic stroke were consecutively and prospectively included. Baseline demographic and clinical covariates were collected and analyzed according to the occurrence and location of CMBs and levels of blood glucose. Results: Of 161 patients included in the final analysis, 69 (42.76%) were women. A total of 80 patients (49.69%) had CMBs. There was a significant trend towards the prevalence of CMBs with increasing glucose quarter (p = 0.001). Post hoc analysis showed the rate of prevalence of CMBs to be significantly higher in the third quarter (OR 1.90, 95% CI 1.20–3.02) and fourth quarter (OR 1.65, 95% CI 1.21–2.25) than that in the first. The frequencies of deep or infratentorial CMBs differed with glucose quarter. Post hoc analysis showed that frequencies of deep or infratentorial CMBs were significantly more frequent in the third quarter (OR 1.76, 95% CI 1.06–2.87) and fourth quarter (OR 1.65, 95% CI 1.19–2.31) than those in the first. Conclusions: In this prospective study of patients with acute ischaemic stroke, our results showed that glucose was associated with deep or infratentorial CMBs but not with lobar CMBs.

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“…Nonalcoholic steatohepatitis (NASH) has emerged as the most common chronic liver disease and, as expected, is a leading indication for liver transplantation and the major cause of hepatocellular carcinoma . In addition to intrahepatic damage, NASH increases an individual’s risk of cardiovascular and metabolic diseases . A lack of effective treatments has spurred investigators to explore therapeutic targets for treating NASH.…”

mentioning

confidence: 99%

F‐box/WD Repeat‐Containing Protein 5 Mediates the Ubiquitination of Apoptosis Signal‐Regulating Kinase 1 and Exacerbates Nonalcoholic Steatohepatitis in Mice

Bai

Chen

et al. 2019

Hepatology

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Inhibition of apoptosis signal‐regulating kinase 1 (ASK1) activation has emerged as a promising target for the treatment of nonalcoholic steatohepatitis (NASH). Multiple forms of posttranslational modifications determine the activity of ASK1. In addition to phosphorylation, recent studies revealed that ubiquitination is essential for ASK1 activation. However, the endogenous factor that regulates ASK1 ubiquitination and activation remains poorly defined. In this study, we identified the E3 ligase Skp1‐Cul1‐F‐box (SCF) protein F‐box/WD repeat‐containing protein 5 (FBXW5) as a key endogenous activator of ASK1 ubiquitination. FBXW5 is the central component of the SCF complex (SCFFbxw5) that directly interacts with and ubiquitinates ASK1 in hepatocytes during NASH development. An in vivo study showed that hepatocyte‐specific overexpression of FBXW5 exacerbated diet‐induced systemic and hepatic metabolic disorders, as well as the activation of ASK1‐related mitogen‐activated protein kinase (MAPK) signaling in the liver. Conversely, hepatocyte‐specific deletion of FBXW5 significantly prevented the progression of these abnormalities. Mechanically, FBXW5 facilitated the addition of Lys63‐linked ubiquitin to ASK1 and thus exacerbated ASK1‐c‐Jun N‐terminal kinase/p38 MAPK signaling, inflammation, and lipid accumulation. Furthermore, we demonstrated that the N‐terminus (S1) and C‐terminus (S3) of FBXW5 respectively and competitively ablate the function of FBXW5 on ASK1 activation and served as effective inhibitors of NASH progression. Conclusion: This evidence strongly suggests that SCFFbxw5 is an important activator of ASK1 ubiquitination in the context of NASH. The development of FBXW5(S1) or FBXW5(S3)‐mimicking drugs and screening of small‐molecular inhibitors specifically abrogating ASK1 ubiquitination‐dependent activation are viable approaches for NASH treatment.

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Hypertension, diabetes, atherosclerosis and NASH: Cause or consequence?

Cited by 520 publications

References 209 publications

Cardiovascular risk factors in non‐alcoholic fatty liver disease

Cardiovascular risk factors in non‐alcoholic fatty liver disease

Blood Glucose Levels Are Associated with Cerebral Microbleeds in Patients with Acute Ischaemic Stroke

F‐box/WD Repeat‐Containing Protein 5 Mediates the Ubiquitination of Apoptosis Signal‐Regulating Kinase 1 and Exacerbates Nonalcoholic Steatohepatitis in Mice

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