Regulation of lipid storage and inflammation in the liver by CEACAM1

Abstract

This review focuses on a special aspect of hepatic lipid storage and inflammation that occurs during nutritional excess in obesity. Mounting evidence supports that prolonged excess fatty acid (FA) uptake in the liver is strongly associated with hepatic lipid storage and inflammation and that the two processes are closely linked by a homeostatic mechanism. There is also strong evidence that bacterial lipids may enter the gut by a common mechanism with lipid absorption and that there is a set point to determine when their uptake triggers an inflammatory response in the liver. In fact, the progression from high uptake of FAs in the liver resulting in Metabolic dysfunction-associated steatotic liver disease (MASLD) to the development of the more serious Metabolic dysfunction-associated steatohepatitis (MASH) depends on the degree of inflammation and its progression from an acute to a chronic state. Thus, MASLD/MASH implicates both excess fatty acids and progressive inflammation in the aetiology of liver disease. We start the discussion by introduction of CD36, a major player in FA and lipopolysaccharide (LPS) uptake in the duodenum, liver and adipose tissue. We will then introduce CEACAM1, a major player in the regulation of hepatic de novo lipogenesis and the inflammatory response in the liver, and its dual association with CD36 in enterocytes and hepatocytes. We conclude that CEACAM1 and CD36 together regulate lipid droplet formation and inflammation in the liver.

Keywords: CD36; CEACAM1; LPS; fatty liver disease; inflammation.

FIGURE 1

CD36 and Lipid handling during feeding. (1) Enterocytes in the duodenum absorb FAs and LPS via CD36. TGs are emulsified by bile and hydrolyzed into FAs by pancreatic lipase. FAs are converted back to TGs in chylomicrons and VLDL that are secreted into (2) lymphatics that dump into (3) systemic circulation where they are taken up by either (4) the liver that repackages TGs and cholesterol as VLDL and LDL or (5) adipose tissue after lipolysis by lipoprotein lipase (LPL) to FAs that are taken up by CD36 and stored as TGs in lipid droplets. HDL is involved in cholesterol and LPS recycling via the bile.

FIGURE 2

Amino acid sequences of CEACAM1 cytoplasmic isoforms. CEACAM1‐SF (SF) and CEACAM1‐LF (LF) share identical sequences through G458 and thereafter differ due to mRNA splicing at the exon 6–7 boundary (underlined G458). The last two residues of the transmembrane domain are F451‐L452 (magenta) followed by the beginning of the cytoplasmic domain (H453). F454 (green) requires phosphorylation of T457 (red) in the short form by CaMK2D to bind Actin. The two ITIMs (blue) have critical tyrosines at Y493 and Y520 in CEACAM1‐LF. The target sequence phosphorylated by PKA at S512 and by GSK3β at S508 is shown in orange.

FIGURE 3

Location of critical response elements (REs) in the promoters of human (hu) and murine (mu) CEACAM1 genes. The promoter sequences were aligned for maximum homology and compared for REs of Sp1 (blue), Usf1 (yellow), and Irf1 (red). Their locations were verified by LM‐PCR and mutation analysis. Protected areas of the CEACAM1 promoter are shown by coloured triangles. In addition, we have located the putative REs of Bcl6 (purple) and androgen (green) by published studies on Bcl6 in lipid genes and on androgen studies in the rat prostate.

FIGURE 4

Role of ITIMs in huCEACAM1. In hepatic lipid storage versus excretion. During fasting the combination of PKA and GSK3β lead to phosphorylation of S508 that favours Y493 (ITIM‐1) phosphorylation and lipid storage. During feeding, the balance shifts to phosphorylation of Y520 (ITIM‐2) and lipid excretion.

FIGURE 5

Effect of CEACAM1 mutants on BC size. Left to right: WT, S508A and S508D mutants triple stained for CEACAM1 (green), Actin (red) and nuclei (blue), and S508A mutant stained for CD36 (green), Actin (red) and nuclei (blue). Data taken from Chean et al.