Fibrinogen-like protein 2 regulates macrophage glycolytic reprogramming by directly targeting PKM2 and exacerbates alcoholic liver injury.

BACKGROUND & AIMS: Switching of the macrophage activation phenotype affects the pathogenesis of alcoholic liver diseases, and metabolic reprogramming can provide the energy demand for macrophage phenotypes shift. However, the molecular mechanism by which immune metabolism regulates the activation of proinflammatory macrophages remains unclear. APPROACH: Expression of Fgl2 was examined in patients with alcoholic hepatitis and healthy controls. Mice were fed with a Lieber-DeCarli diet. Livers from mice were used to observe liver injury and macrophage activation. Fgl2 overexpressing THP-1 cell was used to find interacting partners through immunoprecipitation plus mass spectrometry. Naive bone marrow derived macrophages stimulated with LPS and ethanol were used for cell experiments. RESULTS: Expression of Fgl2 was elevated in macrophages of livers from mice with chronic-binge ethanol feeding or patients with alcoholic hepatitis. Fgl2 depletion ameliorated ethanol diet-induced hepatic steatosis and oxidative injury as well as the levels of proinflammatory cytokines. Fgl2-/- mice exhibited suppressed M1 polarization and glycolysis pathway activation. Fgl2 interacted with the M2 isoform of pyruvate kinase (PKM2) in macrophages and facilitated PKM2 nuclear translocation, thus promoting glycolysis in M1 macrophages and the secretion of proinflammatory cytokines. Furthermore, Fgl2 overexpression in THP-1 cells enhances PKM2-dependent glycolysis and inflammation, which could be reversed by activation of enzymatic PKM2 using DASA58. CONCLUSIONS: Taken together, Fgl2 hastens the development of alcoholic liver injury by mediating PKM2 dependent aerobic glycolysis in proinflammatory macrophages. Strategies that inhibiting proinflammatory macrophage activation by silencing Fgl2 might be a potential therapeutic intervention for alcoholic liver injury.

Metabolic Syndrome, Nonalcoholic Fatty Liver Disease, and Chronic Hepatitis B: A Narrative Review.

Chronic hepatitis B (CHB) remains a relatively major public health problem. Simultaneously, an unhealthy lifestyle causes a series of metabolic abnormalities, the most critical of which are metabolic syndrome (MS) and nonalcoholic fatty liver disease (NAFLD). Therefore, it is increasingly common for MS and NAFLD to coexist with CHB. MS is a cluster of metabolic disorders, while NAFLD is always considered as the manifestation of MS in the liver. The aim of this article is to review recent advances to explain the complex relationship among MS, NAFLD, and hepatitis B virus (HBV) infection. MS and NAFLD both have obesity and insulin resistance as central factors and both can lead to adverse hepatic and extrahepatic outcomes. However, there is insufficient evidence to associate NAFLD with all components of MS, and genetically related NAFLD has little association with MS. Incidences of MS and NAFLD are inversely associated with HBV infection. However, the effect of HBV infection on the risk of insulin resistance and dyslipidemia is not well understood. Evidence from both clinical studies and animal experiments suggested that hepatic steatosis inhibits HBV replication. MS and NAFLD may have adverse effects on CHB disease progression and prognosis. Furthermore, in related studies of CHB with normal alanine aminotransferase (ALT), the roles of MS and NAFLD should also be emphasized. In conclusion, there are complicated interactions that are not yet fully defined among MS, NAFLD, and CHB. To control chronic liver disease effectively, the relationship among the three must be clarified.

The Role of Metabolic Factors and Steatosis in Treatment-Naïve Patients with Chronic Hepatitis B and Normal Alanine Aminotransferase.

INTRODUCTION: We aimed to elucidate the impact of metabolic syndrome (MS) and nonalcoholic fatty liver disease (NAFLD) on treatment-naïve patients with chronic hepatitis B (CHB) and normal alanine aminotransferase (ALT). METHODS: We analyzed the clinical characteristics of a cross-sectional cohort of treatment-naïve patients with CHB and ALT in the upper limit of normal (ULN) from October 2018 to July 2021. ALT ≤ 0.5 ULN was stratified as low-normal ALT (LNALT) and 0.5 ULN < ALT ≤ ULN as high-normal ALT (HNALT). Transient elastography (TE) was used to evaluate liver steatosis and fibrosis. RESULTS: Among 733 patients with CHB enrolled, 23.1% of them had MS, 37.2% of them had NAFLD, and 5.9% of them had significant fibrosis. The proportions of patients with MS, steatosis, and significant fibrosis in the HNALT group were higher than those in the LNALT group (31.4% vs. 14.1%, p < 0.001; 48.7% vs. 25.2%, p < 0.001; and 8.0% vs. 3.6%, p = 0.013, respectively). Multiple linear regression showed that steatosis (beta = 0.098, p = 0.001) and MS (beta = 0.092, p = 0.002) were independently related to ALT levels in the normal range. Multivariate logistic regression showed that age (OR 1.049, 95% CI 1.012-1.087, p = 0.010), aspartate aminotransferase (AST) (OR 1.059, 95% CI 1.005-1.115, p = 0.030), and severe steatosis (OR 2.559, 95% CI 1.212-5.403, p = 0.014) were independently associated with significant fibrosis. When analyzed in the subgroup of CHB with NAFLD, age (OR 1.060, 95% CI 1.006-1.117, p = 0.029) and severe steatosis (OR 2.962, 95% CI 1.126-7.792, p = 0.028) were still statistically significant. CONCLUSION: The accumulation of MS components exacerbated hepatic steatosis. Severe NAFLD was independently associated with significant fibrosis. This emphasizes the importance of screening for MS and NAFLD in patients with CHB and normal ALT, where a more active intervention may apply.