Crosstalk between Irisin Levels, Liver Fibrogenesis and Liver Damage in Non-Obese, Non-Diabetic Individuals with Non-Alcoholic Fatty Liver Disease

Armandi A, Rosso C, Nicolosi A, Caviglia GP; Abate ML, Olivero A, D’Amato D, Verbero M, Gaggini M, Saracco GM, Ribaldone DG, Leeming DJ, Gastaldelli A, Bugianesi E.      

J Clin Med. 2022 Jan 27;11(3):635. doi: 10.3390/jcm11030635. PMID: 35160087 PMCID: PMC8837035

Abstract

Background: Insulin resistance plays a relevant role in the onset of non-alcoholic fatty liver disease (NAFLD) and its progression to non-alcoholic steatohepatitis (NASH) and fibrosis. Irisin is an exercise-induced myokine involved in the regulation of energy homeostasis and glucose metabolism. Additionally, pre-clinical models have shown a potential role of irisin in the pathogenesis of NAFLD. The aim of this study is to explore the association between irisin, histological features and biomarkers of liver fibrogenesis in non-diabetic, non-obese, biopsy-proven NAFLD individuals.

Methods: Forty-one patients with histological evidence of NAFLD were included. Circulating irisin and direct markers of fibrogenesis N-terminal type III collagen propeptide (PRO-C3) and type VI collagen cleavage product (PRO-C6) were measured by ELISA.

Results: Median age of the cohort was 45 years (41-51) and 80.4% were male. Significant fibrosis (stage ≥ 2) was present in 36.6% of cases. Circulating irisin, PRO-C3 and PRO-C6 levels were significantly higher in subjects with fibrosis stage ≥ 2 when compared to those with fibrosis stage < 2 (5.96 ng/mL (95% CI = 4.42-9.19) vs. 2.42 ng/mL (95% CI = 1.73-5.95), p = 0.033; 9.5 ng/mL (95% CI = 7.7-13.6) vs. 6.2 ng/mL (95% CI = 4.9-8.9), p = 0.016; 6.6 ng/mL (95% CI = 5.6-7.9) vs. 5.1 ng/mL (95% CI = 4.2-5.4), p = 0.013, respectively). Irisin levels were similarly distributed between the features of NASH. Circulating irisin positively correlated with both PRO-C3 and PRO-C6 levels (r = 0.47, p = 0.008 and r = 0.46, p = 0.002).

Conclusions: Increased circulating irisin levels may identify a more aggressive phenotype of liver disease with increased fibrogenesis and more severe liver damage.

Keywords: NAFLD; PRO-C3; PRO-C6; insulin resistance; irisin; liver fibrogenesis; liver fibrosis; non-invasive biomarkers.

MicroRNA 146a is associated with diabetic complications in type 1 diabetic patients from the EURODIAB PCS

Barutta F, Corbetta B, Bellini S, Guarrera S, Matullo G, Scandella M, Schalkwijk C, Stehouwer CD, Chaturvedi N, Soedamah-Muthu SS, Durazzo M, Gruden G.     

J Transl Med. 2021 Nov 25;19(1):475. doi: 10.1186/s12967-021-03142-4.

Abstract

Background: MicroRNA-146a-5p (miR-146a-5p) is a key regulator of inflammatory processes. Expression of miR-146a-5p is altered in target organs of diabetic complications and deficiency of miR-146a-5p has been implicated in their pathogenesis. We investigated if serum miR-146a-5p levels were independently associated with micro/macrovascular complications of type 1 diabetes (DM1).

Methods: A nested case-control study from the EURODIAB PCS of 447 DM1 patients was performed. Cases (n = 294) had one or more complications of diabetes, whereas controls (n = 153) did not have any complication. Total RNA was isolated from all subjects and miR-146a-5p levels measured by qPCR. Both the endogenous controls U6 snRNA and the spike (Cel-miR-39) were used to normalize the results. Logistic regression analysis was carried out to investigate the association of miR-146a-5p with diabetes complications.

Results: MiR-146a-5p levels were significantly lower in cases [1.15 (0.32-3.34)] compared to controls [1.74 (0.44-6.74) P = 0.039]. Logistic regression analysis showed that levels of miR-146a-5p in the upper quartile were inversely associated with reduced odds ratio (OR) of all complications (OR 0.34 [95% CI 0.14-0.76]) and particularly with cardiovascular diseases (CVD) (OR 0.31 [95% CI 0.11-0.84]) and diabetic retinopathy (OR 0.40 [95% CI 0.16-0.99]), independently of age, sex, diabetes duration, A1c, hypertension, AER, eGFR, NT-proBNP, and TNF-α.

Conclusions: In this large cohort of DM1 patients, we reported an inverse and independent association of miR-146a-5p with diabetes chronic complications and in particular with CVD and retinopathy, suggesting that miR-146a-5p may be a novel candidate biomarker of DM1 complications.

Keywords: Cardiovascular diseases; MicroRNAs; Retinopathy; Type 1 diabetes.

Long-term outcomes and predictive ability of non-invasive scoring systems in patients with non-alcoholic fatty liver disease.

Younes R, Caviglia GP, Govaere O, Rosso C, Armandi A, Sanavia T, Pennisi G, Liguori A, Francione P, Gallego-Durán R, Ampuero J, Garcia Blanco MJ, Aller R, Tiniakos D, Burt A, David E, Vecchio FM, Maggioni M, Cabibi D, Pareja MJ, Zaki MYW, Grieco A, Fracanzani AL, Valenti L, Miele L, Fariselli P, Petta S, Romero-Gomez M, Anstee QM, Bugianesi E.

J Hepatol. 2021 Oct;75(4):786-794. doi: 10.1016/j.jhep.2021.05.008. Epub 2021 Jun 4.

Abstract

Background & aims: Non-invasive scoring systems (NSS) are used to identify patients with non-alcoholic fatty liver disease (NAFLD) who are at risk of advanced fibrosis, but their reliability in predicting long-term outcomes for hepatic/extrahepatic complications or death and their concordance in cross-sectional and longitudinal risk stratification remain uncertain.

Methods: The most common NSS (NFS, FIB-4, BARD, APRI) and the Hepamet fibrosis score (HFS) were assessed in 1,173 European patients with NAFLD from tertiary centres. Performance for fibrosis risk stratification and for the prediction of long-term hepatic/extrahepatic events, hepatocarcinoma (HCC) and overall mortality were evaluated in terms of AUC and Harrell's c-index. For longitudinal data, NSS-based Cox proportional hazard models were trained on the whole cohort with repeated 5-fold cross-validation, sampling for testing from the 607 patients with all NSS available.

Results: Cross-sectional analysis revealed HFS as the best performer for the identification of significant (F0-1 vs. F2-4, AUC = 0.758) and advanced (F0-2 vs. F3-4, AUC = 0.805) fibrosis, while NFS and FIB-4 showed the best performance for detecting histological cirrhosis (range AUCs 0.85-0.88). Considering longitudinal data (follow-up between 62 and 110 months), NFS and FIB-4 were the best at predicting liver-related events (c-indices>0.7), NFS for HCC (c-index = 0.9 on average), and FIB-4 and HFS for overall mortality (c-indices >0.8). All NSS showed limited performance (c-indices <0.7) for extrahepatic events.

Conclusions: Overall, NFS, HFS and FIB-4 outperformed APRI and BARD for both cross-sectional identification of fibrosis and prediction of long-term outcomes, confirming that they are useful tools for the clinical management of patients with NAFLD at increased risk of fibrosis and liver-related complications or death.

Lay summary: Non-invasive scoring systems are increasingly being used in patients with non-alcoholic fatty liver disease to identify those at risk of advanced fibrosis and hence clinical complications. Herein, we compared various non-invasive scoring systems and identified those that were best at identifying risk, as well as those that were best for the prediction of long-term outcomes, such as liver-related events, liver cancer and death.

Keywords: APRI; BARD; FIB-4; HFS; NASH; NFS; NSS.

Insulin Resistance across the Spectrum of Nonalcoholic Fatty Liver Disease

Armandi A, Rosso C, Caviglia GP, Bugianesi E.

Metabolites. 2021 Mar 8;11(3):155. doi: 10.3390/metabo11030155.

Abstract

Insulin resistance (IR) is defined as a lower-than-expected response to insulin action from target tissues, leading to the development of type 2 diabetes through the impairment of both glucose and lipid metabolism. IR is a common condition in subjects with nonalcoholic fatty liver disease (NAFLD) and is considered one of the main factors involved in the pathogenesis of nonalcoholic steatohepatitis (NASH) and in the progression of liver disease. The liver, the adipose tissue and the skeletal muscle are major contributors for the development and worsening of IR. In this review, we discuss the sites and mechanisms of insulin action and the IR-related impairment along the spectrum of NAFLD, from simple steatosis to progressive NASH and cirrhosis.

Adipocyte-derived extracellular vesicles regulate survival and function of pancreatic β cells

Iacopo Gesmundo, Barbara Pardini, Eleonora Gargantini, Giacomo Gamba, Giovanni Birolo, Alessandro Fanciulli, Dana Banfi, Noemi Congiusta, Enrica Favaro, Maria Chiara Deregibus, Gabriele Togliatto , Gaia Zocaro, Maria Felice Brizzi, Raul M Luque, Justo P Castaño, Maria Alessandra Bocchiotti8, Simone Arolfo, Stefania Bruno, Rita Nano, Mario Morino , Lorenzo Piemonti, Huy Ong , Giuseppe Matullo , Juan M Falcón-Pérez, Ezio Ghigo, Giovanni Camussi, Riccarda Granata

JCI Insight. 2021 Mar 8;6(5):e141962. doi: 10.1172/jci.insight.141962.

Abstract

Extracellular vesicles (EVs) are implicated in the crosstalk between adipocytes and other metabolic organs, and an altered biological cargo has been observed in EVs from human obese adipose tissue (AT). Yet, the role of adipocyte-derived EVs in pancreatic β cells remains to be determined. Here, we explored the effects of EVs released from adipocytes isolated from both rodents and humans and human AT explants on survival and function of pancreatic β cells and human pancreatic islets. EVs from healthy 3T3-L1 adipocytes increased survival and proliferation and promoted insulin secretion in INS-1E β cells and human pancreatic islets, both those untreated or exposed to cytokines or glucolipotoxicity, whereas EVs from inflamed adipocytes caused β cell death and dysfunction. Human lean adipocyte-derived EVs produced similar beneficial effects, whereas EVs from obese AT explants were harmful for human EndoC-βH3 β cells. We observed differential expression of miRNAs in EVs from healthy and inflamed adipocytes, as well as alteration in signaling pathways and expression of β cell genes, adipokines, and cytokines in recipient β cells. These in vitro results suggest that, depending on the physiopathological state of AT, adipocyte-derived EVs may influence β cell fate and function.

Keywords: Adipose tissue; Beta cells; Diabetes; Metabolism.

The Impact of Dysmetabolic Sarcopenia Among Insulin Sensitive Tissues: A Narrative Review

Angelo Armandi , Chiara Rosso , Gian Paolo Caviglia , Davide Giuseppe Ribaldone , Elisabetta Bugianesi

Front Endocrinol (Lausanne). 2021 Nov 10;12:716533. doi: 10.3389/fendo.2021.716533. eCollection 2021.

Abstract

Sarcopenia is a common muscular affection among elderly individuals. More recently, it has been recognized as the skeletal muscle (SM) expression of the metabolic syndrome. The prevalence of sarcopenia is increasing along with visceral obesity, to which it is tightly associated. Nonetheless, it is a still underreported entity by clinicians, despite the worsening in disease burden and reduced patient quality of life. Recognition of sarcopenia is clinically challenging, and variability in study populations and diagnostic methods across the clinical studies makes it hard to reach a strong evidence. Impaired insulin activity in SM is responsible for the altered molecular pathways and clinical manifestations of sarcopenia, which is morphologically expressed by myosteatosis. Lipotoxicity, oxidative stress and adipose tissue-derived inflammation lead to both alterations in glucose disposal and protein synthesis in SM, with raising insulin resistance (IR) and SM atrophy. In particular, hyperleptinemia and leptin resistance interfere directly with SM activity, but also with the release of Growth Hormone from the hypohysis, leading to a lack in its anabolic effect on SM. Moreover, sarcopenia is independently associated to liver fibrosis in Non-Alcoholic Fatty Liver Disease (NAFLD), which in turn worsens SM functionality through the secretion of proinflammatory heptokines. The cross-talk between the liver and SM in the IR setting is of crucial relevance, given the high prevalence of NAFLD and the reciprocal impact of insulin-sensitive tissues on the overall disease burden. Along with the efforts of non-invasive diagnostic approaches, irisin and myostatin are two myokines currently evaluated as potential biomarkers for diagnosis and prognostication. Decreased irisin levels seem to be potentially associated to sarcopenia, whereas increased myostatin has shown to negatively impact on sarcopenia in pre-clinical studies. Gene variants in irisin have been explored with regard to the impact on the liver disease phenotype, with conflicting results. The gut-muscle axis has gain relevance with the evidence that insulin resistance-derived gut dysbiosis is responsible for increased endotoxemia and reduction in short-chain free fatty acids, directly affecting and predisposing to sarcopenia. Based on the current evidence, more efforts are needed to increase awareness and improve the management of sarcopenic patients.