Loss of CEACAM1 in hepatocytes causes hepatic fibrosis.

Background: The role of insulin resistance in hepatic fibrosis in Metabolic dysfunction-Associated SteatoHepatitis (MASH) remains unclear. Carcinoembryonic Antigen-related Cell Adhesion Molecule1 protein (CEACAM1) promotes insulin clearance to maintain insulin sensitivity and repress de novo lipogenesis, as bolstered by the development of insulin resistance and steatohepatitis in AlbuminCre + Cc1 mice with liver-specific mouse gene encoding CEACAM1 protein (Ceacam1) deletion. We herein investigated whether these mice also developed hepatic fibrosis and whether hepatic CEACAM1 is reduced in patients with MASH at different fibrosis stages.

Loss of CEACAM1 in endothelial cells causes hepatic fibrosis.

Objectives: Hepatocytic CEACAM1 plays a critical role in NASH pathogenesis, as bolstered by the development of insulin resistance, visceral obesity, steatohepatitis and fibrosis in mice with global Ceacam1 (Cc1) deletion. In contrast, VECadCre+Cc1 mice with endothelial loss of Cc1 manifested insulin sensitivity with no visceral obesity despite elevated NF-κB signaling and increased systemic inflammation. We herein investigated whether VECadCre+Cc1 male mice develop hepatic fibrosis and whether this is mediated by increased production of endothelin1 (ET1), a transcriptional NF-κB target.

De novo lipogenesis in non-alcoholic fatty liver disease: Quantification with stable isotope tracers.

Background: Non-alcoholic fatty liver disease (NAFLD) is characterized as an abnormal accumulation of triglyceride in hepatocytes. Hepatic de novo lipogenesis may play an important role in the accumulation of lipids in the liver during NAFLD. Due to the importance of lipid biosynthetic fluxes in NAFLD and T2D, tracer methodologies have been developed for their study and quantification.

Loss of postprandial insulin clearance control by Insulin-degrading enzyme drives dysmetabolism traits.

Systemic insulin availability is determined by a balance between beta-cell secretion capacity and insulin clearance (IC). Insulin-degrading enzyme (IDE) is involved in the intracellular mechanisms underlying IC. The liver is a major player in IC control yet the role of hepatic IDE in glucose and lipid homeostasis remains unexplored.

Transfer of glucose hydrogens via acetyl-CoA, malonyl-CoA, and NADPH to fatty acids during de novo lipogenesis.

Deuterated water (HO) is widely used for measuring de novo lipogenesis (DNL). H is incorporated into fatty acids via exchange between body water and the hydrogens of acetyl-CoA, malonyl-CoA, and NADPH. Previous studies concluded that these exchanges are incomplete; therefore, fatty acid H enrichment requires correcting.

Rho-kinase/AMPK axis regulates hepatic lipogenesis during overnutrition.

Obesity is a major risk factor for developing nonalcoholic fatty liver disease (NAFLD). NAFLD is the most common form of chronic liver disease and is closely associated with insulin resistance, ultimately leading to cirrhosis and hepatocellular carcinoma. However, knowledge of the intracellular regulators of obesity-linked fatty liver disease remains incomplete.

Sources of hepatic glycogen synthesis in mice fed with glucose or fructose as the sole dietary carbohydrate.

Purpose: The positional analysis of hepatic glycogen enrichment from deuterated water ( H O) by H NMR has been applied previously to resolve the contributions of glucose and fructose to glycogen synthesis in rodents fed a high sucrose diet. To further validate this method, this analysis was applied to mice fed with synthetic diets whose carbohydrate components consisted solely of either glucose or fructose.

Methods: Eight glucose-fed and 12 fructose-fed mice were given H O followed by ad libitum feeding overnight.