Molecular mechanisms of metabolic dysfunction-associated steatotic liver disease (MASLD): functional analysis of glucose and fructose metabolism pathways

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a major non-communicable disease with global prevalence of 38% and no early-stage treatment. It has risk factors of insulin resistance, impaired glucose tolerance, type 2 diabetes, and diets rich in glucose and fructose. In this review, we explore evidence of abnormal increased early-stage glycolytic intermediates, glycolytic overload, in the initiation of MASLD and propose a new strategy for improved therapy. Glucose is mainly metabolized to glucose-6-phosphate by glucokinase (GCK) in the human liver. This is slowed by the competitive inhibitor, glucokinase regulatory protein (GKRP), with inhibition potentiated by fructose-6-phosphate and lifted by fructose-1-phosphate. The in situ activity of GCK is predicted to increase up to 3-fold by dietary glucose and over 4-fold with concurrent fructose. Related increased glycolytic intermediates activate carbohydrate response element binding protein (ChREBP), hexosamine pathway, and methylglyoxal-stimulated unfolded protein response (UPR). Activation of ChREBP contributes to enhanced lipogenesis and impaired suppression of hepatic glucose production by down-regulation of insulin receptor substrate-2 (IRS-2). IRS-1 signaling is maintained, contributing to enhanced lipogenesis through activation of sterol response element binding protein-1c and down-regulation of IRS-2. Hexosamine pathway activity stabilizes GCK and ChREBP to proteolysis, and the UPR stimulates inflammation and fibrosis. Hepatocytes then export glucose excessively, increasing fasting plasma glucose and risk of peripheral insulin resistance, type 2 diabetes, and vascular complications. Activators of nuclear factor erythroid 2-related factor 2 (Nrf2) provide a novel strategy for therapy. They divert excess glucose metabolism to the pentosephosphate pathway, decreasing activation of ChREBP and hexosamine pathway and formation of methylglyoxal, and decrease lipogenic gene expression. Nrf2 activator, trans-resveratrol and hesperetin combination, corrected glycolytic overload and insulin resistance clinically and now merits evaluation for early-stage treatment of MASLD.