Targeting cell death in NAFLD: mechanisms and targeted therapies.

Nonalcoholic fatty liver disease (NAFLD) is a group of chronic liver disease which ranges from simple steatosis (NAFL) to non-alcoholic steatohepatitis (NASH) and is characterized by lipid accumulation, inflammation activation, fibrosis, and cell death. To date, a number of preclinical studies or clinical trials associated with therapies targeting fatty acid metabolism, inflammatory factors and liver fibrosis are performed to develop effective drugs for NAFLD/NASH. However, few therapies are cell death signaling-targeted even though the various cell death modes are present throughout the progression of NAFLD/NASH. Here we summarize the four types of cell death including apoptosis, necroptosis, pyroptosis, and ferroptosis in the NAFLD and the underlying molecular mechanisms by which the pathogenic factors such as free fatty acid and LPS induce cell death in the pathogenesis of NAFLD. In addition, we also review the effects of cell death-targeted therapies on NAFLD. In summary, our review provides comprehensive insight into the roles of various cell death modes in the progression of NAFLD, which we hope will open new avenues for therapeutic intervention.

Xu HL ，Wan SR ，An Y ，Wu Q ，Xing YH ，Deng CH ，Zhang PP ，Long Y ，Xu BT ，Jiang ZZ ... -  《Cell Death Discovery》

Metabolic signatures across the full spectrum of non-alcoholic fatty liver disease.

Non-alcoholic fatty liver disease (NAFLD) is a progressive liver disease with potentially severe complications including cirrhosis and hepatocellular carcinoma. Previously, we have identified circulating lipid signatures associating with liver fat content and non-alcoholic steatohepatitis (NASH). Here, we develop a metabolomic map across the NAFLD spectrum, defining interconnected metabolic signatures of steatosis (non-alcoholic fatty liver, NASH, and fibrosis). We performed mass spectrometry analysis of molecular lipids and polar metabolites in serum samples from the European NAFLD Registry patients (n = 627), representing the full spectrum of NAFLD. Using various univariate, multivariate, and machine learning statistical approaches, we interrogated metabolites across 3 clinical perspectives: steatosis, NASH, and fibrosis. Following generation of the NAFLD metabolic network, we identify 15 metabolites unique to steatosis, 18 to NASH, and 15 to fibrosis, with 27 common to all. We identified that progression from F2 to F3 fibrosis coincides with a key pathophysiological transition point in disease natural history, with n = 73 metabolites altered. Analysis of circulating metabolites provides important insights into the metabolic changes during NAFLD progression, revealing metabolic signatures across the NAFLD spectrum and features that are specific to NAFL, NASH, and fibrosis. The F2-F3 transition marks a critical metabolic transition point in NAFLD pathogenesis, with the data pointing to the pathophysiological importance of metabolic stress and specifically oxidative stress. The study is registered at Clinicaltrials.gov (NCT04442334). Non-alcoholic fatty liver disease is characterised by the build-up of fat in the liver, which progresses to liver dysfunction, scarring, and irreversible liver failure, and is markedly increasing in its prevalence worldwide. Here, we measured lipids and other small molecules (metabolites) in the blood with the aim of providing a comprehensive molecular overview of fat build-up, liver fibrosis, and diagnosed severity. We identify a key metabolic 'watershed' in the progression of liver damage, separating severe disease from mild, and show that specific lipid and metabolite profiles can help distinguish and/or define these cases.

McGlinchey AJ ，Govaere O ，Geng D ，Ratziu V ，Allison M ，Bousier J ，Petta S ，de Oliviera C ，Bugianesi E ，Schattenberg JM ，Daly AK ，Hyötyläinen T ，Anstee QM ，Orešič M ... -  《-》

Hepatic transcriptome signatures in patients with varying degrees of nonalcoholic fatty liver disease compared with healthy normal-weight individuals.

Suppli MP ，Rigbolt KTG ，Veidal SS ，Heebøll S ，Eriksen PL ，Demant M ，Bagger JI ，Nielsen JC ，Oró D ，Thrane SW ，Lund A ，Strandberg C ，Kønig MJ ，Vilsbøll T ，Vrang N ，Thomsen KL ，Grønbæk H ，Jelsing J ，Hansen HH ，Knop FK ... -  《-》

LC-MS-based lipidomic analysis in distinguishing patients with nonalcoholic steatohepatitis from nonalcoholic fatty liver.

Nonalcoholic fatty liver disease (NAFLD) is one of the main liver diseases, and its pathologic profile includes nonalcoholic fatty liver (NAFL) and nonalcoholic steatohepatitis (NASH). However, there is no reliable non-invasive parameter in distinguishing NASH from NAFL in clinical practice. The present study was to find a non-invasive way to differentiate these two categories of NAFLD via lipidomic analysis. Lipidomic analysis was used to determine the changes of lipid moieties in blood from 20 NAFL and 10 NASH patients with liver biopsy. Liver histology was evaluated after hematoxylin and eosin staining and Masson's trichrome staining. The profile of lipid metabolites in correlation with steatosis, inflammation, hepatocellular necroptosis, fibrosis, and NAFLD activity score (NAS) was analyzed. Compared with NAFL patients, NASH patients had higher degree of steatosis, ballooning degeneration, lobular inflammation. A total of 434 different lipid molecules were identified, which were mainly composed of various phospholipids and triacylglycerols. Many lipids, such as phosphatidylcholine (PC) (P-22:0/18:1), sphingomyelin (SM) (d14:0/18:0), SM (d14:0/24:0), SM (d14:0/22:0), phosphatidylethanolamine (PE) (18:0/22:5), PC (O-22:2/12:0), and PC (26:1/11:0) were elevated in the NASH group compared to those in the NAFL group. Specific analysis revealed an overall lipidomic profile shift from NAFL to NASH, and identified valuable lipid moieties, such as PCs [PC (14:0/18:2), PE (18:0/22:5) and PC (26:1/11:0)] or plasmalogens [PC (O-22:0/0:0), PC (O-18:0/0:0), PC (O-16:0/0:0)], which were significantly altered in NASH patients. In addition, PC (14:0/18:2), phosphatidic acid (18:2/24:4) were positively correlated with NAS; whereas PC (18:0/0:0) was correlated positively with fibrosis score. The present study revealed overall lipidomic profile shift from NAFL to NASH, identified valuable lipid moieties which may be non-invasive biomarkers in the categorization of NAFLD. The correlations between lipid moieties and NAS and fibrosis scores indicate that these lipid biomarkers may be used to predict the severity of the disease.

Wang ZH ，Zheng KI ，Wang XD ，Qiao J ，Li YY ，Zhang L ，Zheng MH ，Wu J ... -  《Hepatobiliary & Pancreatic Diseases International》

Excess Body Weight and Metabolic (Dysfunction)-Associated Fatty Liver Disease (MAFLD).

Nonalcoholic fatty liver disease (NAFLD) describes a continuum of liver abnormalities from simple nonalcoholic fatty liver (NAFL) to nonalcoholic fatty liver hepatitis or steatohepatitis (NASH) to NASH fibrosis. It has a variable course, but just like alcoholic fatty liver disease, it can lead to liver cirrhosis and cancer (hepatocellular carcinoma). NAFLD is a clinical entity characterized by the presence of liver steatosis, which affects at least 5% of hepatocytes. Affected are people who consume little or no alcohol and who have no secondary cause of liver steatosis such as viral hepatitis, drug intake (e.g., tamoxifen, amiodarone, methotrexate, etc.), or lipodystrophy. NAFLD is, nowadays, the most common liver disease in Europe, with an estimated prevalence of 25%. The currently widely recognized recommendation for the therapy of NAFLD is a lifestyle modification with the goal of weight loss. Although no drugs are currently approved for the treatment of NAFLD, several candidates are in clinical trials. Besides weight loss and physical activity, corresponding single active ingredients or combination therapies are intended to stop the progression of the disease and, in the best case, reverse it. The newly propagated name MAFLD (metabolic-associated fatty liver disease) should indicate that the disease is associated with metabolic disorders. The term MAFLD also implies multiple overlapping causes and drivers of this soaring disease. The prevalence of NAFLD continues to rise worldwide. NAFLD, NASH, and fibrosis in NAFLD occur predominantly in patients with obesity and type 2 diabetes (T2DM) or else precede these conditions. The progression of NAFLD is highly dependent on changes in glucose, lipid metabolism, and fibrogenesis. A new definition and nomenclature of fatty liver disease, "metabolic associated fatty liver disease" (MAFLD), should be discussed carefully, since around 40% of the global population with NAFLD are classified as non-obese and almost 1/5 as lean. Since the pathogenesis of fatty liver disease, obesity, and glucose and lipid metabolism diseases are very closely related, it is important to continue to look for mechanisms that these diseases have in common and develop new therapeutic approaches.

Roeb E 《-》