PPARγ signaling in hepatocarcinogenesis: Mechanistic insights for cellular reprogramming and therapeutic implications.

Liver cancer or hepatocellular carcinoma (HCC) is leading cause of cancer-related mortalities globally. The therapeutic approaches for chronic liver diseases-associated liver cancers aimed at modulating immune check-points and peroxisome proliferator-activated receptor gamma (PPARγ) signaling pathway during multistep process of hepatocarcinogenesis that played a dispensable role in immunopathogenesis and outcomes of disease. Herein, the review highlights PPARγ-induced effects in balancing inflammatory (tumor necrosis factor alpha (TNF-α), interleukin (IL)-6, IL-1) and anti-inflammatory cytokines (IL-10, transforming growth factor beta (TGF-ß), and interplay of PPARγ, hepatic stellate cells and fibrogenic niche in cell-intrinsic and -extrinsic crosstalk of hepatocarcinogenesis. PPARγ-mediated effects in pre-malignant microenvironment promote growth arrest, cell senescence and cell clearance in liver cancer pathophysiology. Furthermore, PPARγ-immune cell axis of liver microenvironment exhibits an immunomodulation strategy of resident immune cells of the liver (macrophages, natural killer cells, and dendritic cells) in concomitance with current clinical guidelines of the European Association for Study of Liver Diseases (EASL) for several liver diseases. Thus, mechanistic insights of PPARγ-associated high value targets and canonical signaling suggest PPARγ as a possible therapeutic target in reprogramming of hepatocarcinogenesis to decrease burden of liver cancers, worldwide.

COVID-19 and comorbidities of hepatic diseases in a global perspective.

The worldwide outbreak of coronavirus disease 2019 (COVID-19) has challenged the priorities of healthcare system in terms of different clinical management and infection transmission, particularly those related to hepatic-disease comorbidities. Epidemiological data evidenced that COVID-19 patients with altered liver function because of hepatitis infection and cholestasis have an adverse prognosis and experience worse health outcomes. COVID-19-associated liver injury is correlated with various liver diseases following a severe acute respiratory syndrome-coronavirus type 2 (SARS-CoV-2) infection that can progress during the treatment of COVID-19 patients with or without pre-existing liver disease. SARS-CoV-2 can induce liver injury in a number of ways including direct cytopathic effect of the virus on cholangiocytes/hepatocytes, immune-mediated damage, hypoxia, and sepsis. Indeed, immediate cytopathogenic effects of SARS-CoV-2 via its potential target, the angiotensin-converting enzyme-2 receptor, which is highly expressed in hepatocytes and cholangiocytes, renders the liver as an extra-respiratory organ with increased susceptibility to pathological outcomes. But, underlying COVID-19-linked liver disease pathogenesis with abnormal liver function tests (LFTs) is incompletely understood. Hence, we collated COVID-19-associated liver injuries with increased LFTs at the nexus of pre-existing liver diseases and COVID-19, and defining a plausible pathophysiological triad of COVID-19, hepatocellular damage, and liver disease. This review summarizes recent findings of the exacerbating role of COVID-19 in pre-existing liver disease and vice versa as well as international guidelines of clinical care, management, and treatment recommendations for COVID-19 patients with liver disease.

Adiponectin and PPAR: a setup for intricate crosstalk between obesity and non-alcoholic fatty liver disease.

Adiponectin, a soluble adipocytokine, plays an important role in the functioning of adipose tissue and in the regulation of inflammation, particularly hepatic inflammation. The adiponectin subsequently imparts a crucial role in metabolic and hepato-inflammatory diseases. The most recent evidences indicate that lipotoxicity-induced inflammation in the liver is associated with obesity-derived alterations and remolding in adipose tissue that culminates in most prevalent liver pathology named as non-alcoholic fatty liver disease (NAFLD). A comprehensive crosstalk of adiponectin and its cognate receptors, specifically adiponectin receptor-2 in the liver mediates ameliorative effects in obesity-induced NAFLD by interaction with hepatic peroxisome proliferator-activated receptors (PPARs). Recent studies highlight the implication of molecular mediators mainly involved in the pathogenesis of obesity and obesity-driven NAFLD, however, the plausible mechanisms remain elusive. The present review aimed at collating the data regarding mechanistic approaches of adiponectin and adiponectin-activated PPARs as well as PPAR-induced adiponectin levels in attenuation of hepatic lipoinflammation. Understanding the rapidly occurring adiponectin-mediated pathophysiological outcomes might be of importance in the development of new therapies that can potentially resolve obesity and obesity-associated NAFLD.

Psychosocial-Stress, Liver Regeneration and Weight Gain: a Conspicuous Pathophysiological Triad.

Psychosocial stress alters several physiological parameters resulting in multiple disorders, particularly compromising the immune system thereby provoking various diseases including liver disorders. However, the plausible underlying mechanisms remain elusive. Recent literature provides mechanistic evidences of detrimental effects of psychosocial stress on physiology of different body organs including liver. The data of stress-induced pathophysiological changes in liver functions and obesity were systematically collected from PubMed, ScienceDirect and the Web of Science Databases published in English. Stress and glucocorticoids (GCs) control food intake and energy expenditure through appetite stimulators neuropeptide Y (NYP) and agouti-related protein (AgRP) in hypothalamus. Principle effectors of the activated hypothalamic-pituitary-adrenal (HPA) axis in response to psychosocial stress are proopiomelanocortin (POMC)-derived adrenocorticotropic hormone (ACTH) and GCs. Stress-induced GCs hyper-secretion triggers glucocorticoid receptor (GR)-dependent transcriptional factor, nuclear factor kappa B (NFκB), which interferes TNFα-IL6 and keap1-Nrf2 pathways in liver regeneration and obesity through fine-tuning of TNFα, IL6 and Nrf2 signaling. In this review, it is contrived upon existing evidence to put forward a model whereby exposure to life-stress has a prominent impact over weight gain and can alter the regenerative mode of a damaged liver through Keap1-Nrf2 and TNFa-IL6 pathways.