In addition to causing cirrhosis and hepatocellular carcinoma, hepatitis C virus (HCV) is thought to cause hypolipidemia, hepatic steatosis, insulin resistance, metabolic syndrome, and diabetes. The viral life cycle of HCV depends on cholesterol metabolism in host cells. HCV core protein and nonstructural protein 5A perturb crucial lipid and glucose pathways, such as the sterol regulatory element-binding protein pathway and the protein kinase B/mammalian target of rapamycin/S6 kinase 1 pathway. Although several lines of transgenic mice expressing core or full HCV proteins exhibit hepatic steatosis and/or dyslipidemia, whether they completely reflect the metabolic alterations in humans with HCV infection remains unknown. Many cross-sectional studies have demonstrated increased prevalences of metabolic alterations and cardiovascular events in patients with chronic hepatitis C (CHC); however, conflicting results exist, primarily due to unavoidable individual variations. Utilizing anti-HCV therapy, most longitudinal cohort studies of CHC patients have demonstrated the favorable effects of viral clearance in attenuating metabolic alterations and cardiovascular risks. To determine the risks of HCV-associated metabolic alterations and associated complications in patients with CHC, it is necessary to adjust for crucial confounders, such as HCV genotype and host baseline glucose metabolism, for a long follow-up period after anti-HCV treatment. Adipose tissue is an important endocrine organ due to its release of adipocytokines, which regulate lipid and glucose metabolism. However, most data on HCV infection and adipocytokine alteration are inconclusive. A comprehensive overview of HCV-associated metabolic and adipocytokine alterations, from bench to bedside, is presented in this topic highlight.

Adipose tissue is a highly dynamic endocrine tissue and constitutes a central node in the interorgan crosstalk network through adipokines, which cause pleiotropic effects, including the modulation of angiogenesis, metabolism, and inflammation. Specifically, digestive cancers grow anatomically near adipose tissue. During their interaction with cancer cells, adipocytes are reprogrammed into cancer-associated adipocytes and secrete adipokines to affect tumor cells. Moreover, the liver is the central metabolic hub. Adipose tissue and the liver cooperatively regulate whole-body energy homeostasis via adipokines. Obesity, the excessive accumulation of adipose tissue due to hyperplasia and hypertrophy, is currently considered a global epidemic and is related to low-grade systemic inflammation characterized by altered adipokine regulation. Obesity-related digestive diseases, including gastroesophageal reflux disease, Barrett’s esophagus, esophageal cancer, colon polyps and cancer, non-alcoholic fatty liver disease, viral hepatitis-related diseases, cholelithiasis, gallbladder cancer, cholangiocarcinoma, pancreatic cancer, and diabetes, might cause specific alterations in adipokine profiles. These patterns and associated bases potentially contribute to the identification of prognostic biomarkers and therapeutic approaches for the associated digestive diseases. This review highlights important findings about altered adipokine profiles relevant to digestive diseases, including hepatic, pancreatic, gastrointestinal, and biliary tract diseases, with a perspective on clinical implications and mechanistic explorations.

Hepatic fibrosis is a major cause of morbidity and mortality worldwide, as it ultimately leads to cirrhosis, which is estimated to affect up to 2% of the global population. Hepatic fibrosis is confirmed by liver biopsy, and the erroneous nature of this technique necessitates the search for noninvasive alternatives. However, current biomarker algorithms for hepatic fibrosis have many limitations. Given that the liver is the largest organ and a major metabolic hub in the body, probing the metabolic signature of hepatic fibrosis holds promise for the discovery of new markers and therapeutic targets. Regarding individual metabolic pathways, accumulating evidence shows that hepatic fibrosis leads to alterations in carbohydrate metabolism, as aerobic glycolysis is aggravated in activated hepatic stellate cells (HSCs) and the whole fibrotic liver; in amino acid metabolism, as Fischer’s ratio (branched-chain amino acids/aromatic amino acids) decreases in patients with hepatic fibrosis; and in lipid metabolism, as HSCs lose vitamin A-containing lipid droplets during transdifferentiation, and cirrhotic patients have decreased serum lipids. The current review also summarizes recent findings of metabolic alterations relevant to hepatic fibrosis based on systems biology approaches, including transcriptomics, proteomics, and metabolomics in vitro, in animal models and in humans.

Chronic hepatitis B virus (HBV) infection is a dynamic process involving interactions among HBV, hepatocytes, and the host immune system. The natural course of chronic hepatitis B (CHB) is divided into four chronological phases, including the hepatitis B e antigen (HBeAg)-positive and HBeAg-negative phases. During HBV flare, alanine aminotransferase (ALT) levels abruptly rise to >5× the upper limit of normal; this is thought to occur due to the immune response against an upsurge in serum HBV DNA and antigen levels. Hepatitis flares may occur spontaneously, during or after antiviral therapy, or upon immunosuppression or chemotherapy in both HBeAg-positive and HBeAg-negative patients. The clinical spectrum of HBV flares varies from asymptomatic to hepatic decompensation or failure. HBeAg seroconversion with ≥ 1 year of consolidation therapy is accepted as an endpoint of oral antiviral therapy in HBeAg-positive patients, but recommendations for treating HBeAg-negative patients differ. Thus, the management of HBeAg-negative patients has attracted increasing interest. In the current review, we summarize various types of HBV flares and the associated complex cascade of innate and adaptive immune responses, with a focus on HBeAg-negative CHB patients. Hopefully, this review will provide insight into immunopathogenesis to improve the management of HBV flares in HBeAg-negative CHB patients.

Because the gene expression patterns of nonobese hepatic steatosis in affected patients remain unclear, we sought to explore these patterns using an animal model of nonobese hepatic steatosis.