Role for hepatic CEACAM1 in regulating fatty acid metabolism along the adipocyte-hepatocyte axis

Abstract

Supplementary key words carcinoembryonic antigen-related cell adhesion molecule 1 • insulin resistance • nicotinic acid • lipolysis • insulin clearanceCirculating insulin levels, in part determined by hepatic insulin clearance, regulate insulin action (1-3). Insulin clearance, which occurs mostly in liver and to a lower extent in kidney, but not in skeletal muscle or white adipose tissue (WAT), plays a pivotal role in promoting insulin sensitivity (4). If impaired, it contributes to mounting hyperinsulinemia in obese humans (5, 6), thus constituting a risk factor for metabolic syndrome (7,8).Our studies on the carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1), a transmembrane glycoprotein that is highly expressed in liver and kidney, but not WAT or skeletal muscle (9), support these findings. Upon its phosphorylation by the insulin receptor, CEACAM1 promotes insulin clearance by upregulating receptor-mediated insulin uptake into clathrin-coated pits and degradation in hepatocytes (10). Moreover, it mediates a downregulatory effect on mouse fatty acid synthase Abstract Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) regulates insulin sensitivity by promoting hepatic insulin clearance and mediating suppression of fatty acid synthase activity. Feeding C57BL/6J male mice with a high-fat (HF) diet for 3-4 weeks triggered a >60% decrease in hepatic CEACAM1 levels to subsequently impair insulin clearance and cause systemic insulin resistance and hepatic steatosis. This study aimed at investigating whether lipolysis drives reduction in hepatic CEACAM1 and whether this constitutes a key mechanism leading to diet-induced metabolic abnormalities. Blocking lipolysis with a daily intraperitoneal injection of nicotinic acid in the last two days of a 30-day HF feeding regimen demonstrated that white adipose tissue (WAT)-derived fatty acids repressed hepatic CEACAM1-dependent regulation of insulin and lipid metabolism in 3-month-old male C57BL/6J mice. Adenoviralmediated CEACAM1 redelivery countered the adverse metabolic effect of the HF diet on insulin resistance, hepatic steatosis, visceral obesity, and energy expenditure. It also reversed the effect of HF diet on inflammation and fibrosis in WAT and liver. This assigns a causative role for lipolysis-driven decrease in hepatic CEACAM1 level and its regulation of insulin and lipid metabolism in sustaining systemic insulin resistance, hepatic steatosis, and other abnormalities associated with excessive energy supply.-Russo, L., H. E. Ghadieh, S. S. Ghanem, Q. Y. Al-Share, Z. N. Smiley, C. Gatto-Weis, E. L. Esakov, M. F. McInerney, G. Heinrich, X. Tong, L. Yin, and S. M. Najjar. Role for hepatic CEACAM1 in regulating fatty acid metabolism along the adipocytehepatocyte axis.

Liver-specific reconstitution of CEACAM1 reverses the metabolic abnormalities caused by its global deletion in male mice

“…2). As expected [17], nicotinic acid increased macrophage recruitment to the WAT of all groups (ESM Table 4) to blunt insulin action in the WAT of refed control mice (ESM Fig. 2).…”

“…The critical regulatory role of the loss of hepatic CEACAM1-dependent pathways in these metabolic abnormalities is further demonstrated by the curbed visceral adiposity with associated lipolysis and recruitment of proinflammatory cytokines in Cc1 −/− xliver + mice. This protective metabolic effect of hepatic CEACAM1 is consistent with the prevention of diet-induced insulin resistance and metabolic abnormalities by transgenic overexpression of CEACAM1 in the liver of C57BL/6 mice [15, 34] and by their reversal with liver-specific adenoviral-mediated delivery [17]. …”

“…In some experiments, mice were injected i.p. once daily with nicotinic acid (200 mg/kg body weight per day; Sigma-Aldrich, Saint Louis, MO, USA) for 2 days [17]. Mice were placed in cages with Alpha-dri bedding (Shepherd Specialty Papers, Cincinnati, OH, USA) prior to food removal and phenotyping.…”

“…The liver was extracted, homogenised and incubated in 0.2 mmol/l of [1- 14 C]palmitate (185 × 10 5 Bq) (American Radiolabeled Chemicals, St Louis, MO, USA) and 2 mmol/l ATP [17]. The reaction was terminated with perchloric acid to recover radioactive acid soluble metabolites.…”

“…This suggests that altered fat metabolism plays an important role in sustained insulin resistance. In fact, by inducing human Apolipoprotein A-1 (ApoA-1) [15] and activating the peroxisome proliferation activated receptor (PPARα) that represses Cc1 expression [16], elevated release of NEFAs from adipose tissue maintains ApoA-1-driven expression of the phosphorylation-defective rat S503A CEACAM1 mutant at a higher level than that of the mouse endogenous Cc1 gene, thus, contributing to the dominant-negative effect of the rat Cc1 transgene on insulin clearance in L-SACC1 mice [14, 17]. Whereas this points to the important role of an extrahepatic factor (lipolysis) in the pathogenesis of insulin resistance in L-SACC1 mice, it does not fully explore the primary role of hepatic CEACAM1-dependent insulin clearance pathways in regulating insulin homeostasis and action.…”