, the outbreak of coronavirus disease 2019 (COVID-19), caused by the novel Severe Acute Respiratory Syndrome (SARS) Coronavirus (CoV) 2 (SARS-CoV-2), has led within a few months to a major global health and economic crisis. As of October 2020, more than 40 million confirmed cases have been reported worldwide, with nearly 1 million deaths, affecting 189 countries. 1 The respiratory tract is considered the main target of SARS-CoV-2 infection and a small subset of infected individuals becomes severely ill and may develop acute respiratory distress syndrome (ARDS) with potentially fatal outcome. 2 More recently, systemic features of the disease with the involvement of organs outside the respiratory tract, including the liver and gastrointestinal tract are receiving increasing attention, indicating that COVID-19 may be considered as a systemic infectious and inflammatory disease. 3-7 Although closely related to other Corona virus (CoV) family members SARS-CoV and MERS-CoV (Middle East Respiratory Syndrome CoV), infections with the new SARS-CoV-2 exhibit a different pathological pattern and the mechanistic link between CoVs-induced molecular pathophysiological changes and clinical manifestations remains incompletely understood.

Obesity and type 2 diabetes mellitus (T2DM) are metabolic disorders characterized by metabolic inflexibility with multiple pathological organ manifestations, including non-alcoholic fatty liver disease (NAFLD). Nuclear receptors are ligand-dependent transcription factors with a multifaceted role in controlling many metabolic activities, such as regulation of genes involved in lipid and glucose metabolism and modulation of inflammatory genes. The activity of nuclear receptors is key in maintaining metabolic flexibility. Their activity depends on the availability of endogenous ligands, like fatty acids or oxysterols, and their derivatives produced by the catabolic action of metabolic lipases, most of which are under the control of nuclear receptors. For example, adipose triglyceride lipase (ATGL) is activated by peroxisome proliferator-activated receptor γ (PPARγ) and conversely releases fatty acids as ligands for PPARα, therefore, demonstrating the interdependency of nuclear receptors and lipases. The diverse biological functions and importance of nuclear receptors in metabolic syndrome and NAFLD has led to substantial effort to target them therapeutically. This review summarizes recent findings on the roles of lipases and selected nuclear receptors, PPARs, and liver X receptor (LXR) in obesity, diabetes, and NAFLD.

Background & aims Osteopontin, a multifunctional protein and inflammatory cytokine, is overexpressed in adipose tissue and liver in obesity and contributes to the induction of adipose tissue inflammation and non‐alcoholic fatty liver (NAFL). Studies performed in both mice and humans also point to a potential role for OPN in malignant transformation and tumour growth. To fully understand the role of OPN on the development of NAFL‐derived hepatocellular carcinoma (HCC), we applied a non‐alcoholic steatohepatitis (NASH)‐HCC mouse model on osteopontin‐deficient (Spp1 −/− ) mice analysing time points of NASH, fibrosis and HCC compared to wild‐type mice. Methods Two‐day‐old wild‐type and Spp1 −/− mice received a low‐dose streptozotocin injection in order to induce diabetes, and were fed a high‐fat diet starting from week 4. Different cohorts of mice of both genotypes were sacrificed at 8, 12 and 19 weeks of age to evaluate the NASH, fibrosis and HCC phenotypes respectively. Results Spp1 −/− animals showed enhanced hepatic lipid accumulation and aggravated NASH, as also increased hepatocellular apoptosis and accelerated fibrosis. The worse steatotic and fibrotic phenotypes observed in Spp1 −/− mice might be driven by enhanced hepatic fatty acid influx through CD36 overexpression and by a pathological accumulation of specific diacylglycerol species during NAFL. Lack of osteopontin lowered systemic inflammation, prevented HCC progression to less differentiated tumours and improved overall survival. Conclusions Lack of osteopontin dissociates NASH‐fibrosis severity from overall survival and HCC malignant transformation in NAFLD, and is therefore a putative therapeutic target only for advanced chronic liver disease.

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