Suppressing Hepatic UGT1A1 Increases Plasma Bilirubin, Lowers Plasma Urobilin, Reorganizes Kinase Signaling Pathways and Lipid Species and Improves Fatty Liver Disease

Abstract

Several population studies have observed lower serum bilirubin levels in patients with non-alcoholic fatty liver disease (NAFLD). Yet, treatments to target this metabolic phenotype have not been explored. Therefore, we designed an N-Acetylgalactosamine (GalNAc) labeled RNAi to target the enzyme that clears bilirubin from the blood, the UGT1A1 glucuronyl enzyme (GNUR). In this study, male C57BL/6J mice were fed a high-fat diet (HFD, 60%) for 30 weeks to induce NAFLD and were treated subcutaneously with GNUR or sham (CTRL) once weekly for six weeks while continuing the HFD. The results show that GNUR treatments significantly raised plasma bilirubin levels and reduced plasma levels of the bilirubin catabolized product, urobilin. We show that GNUR decreased liver fat content and ceramide production via lipidomics and lowered fasting blood glucose and insulin levels. We performed extensive kinase activity analyses using our PamGene PamStation kinome technology and found a reorganization of the kinase pathways and a significant decrease in inflammatory mediators with GNUR versus CTRL treatments. These results demonstrate that GNUR increases plasma bilirubin and reduces plasma urobilin, reducing NAFLD and inflammation and improving overall liver health. These data indicate that UGT1A1 antagonism might serve as a treatment for NAFLD and may improve obesity-associated comorbidities.

The associations of psychopathology and metabolic parameters with serum bilirubin levels in patients with acute-episode and drug-free schizophrenia: a 5-year retrospective study using an electronic medical record system

“…Compared to UCB, CB may be more readily separated from albumin to protect patients from metabolism disorders [ 17 ]. Regarding the mechanism of action of bilirubin on glycolipid metabolism, it has been found that bilirubin can reduce glucose and lipid accumulation by increasing insulin sensitivity and intracellular glucose uptake, and activating the aryl hydrocarbon receptor (AhR) signaling pathway [ 60 , 61 ]. A meta-analysis found that the overall prevalence of MetS in patients with schizophrenia was 32.5%, and the prevalence in unmedicated patients was also as high as 20.2% [ 62 ].…”

Loss of carnitine palmitoyltransferase 1a reduces docosahexaenoic acid-containing phospholipids and drives sexually dimorphic liver disease in mice

“…Substrates contained in each array are listed in Supplemental Table 1 . Mouse livers were pooled and measured in triplicate across three chips simultaneously for STK, as previously described in [ [22] , [23] , [24] ]. This approach effectively deals with large batch effects across samples.…”

“…are included in Supplemental Table 2 (males) and 3 (females). MEOW (measurements extensively of winners) plots, as described in [ 24 ], were used to interrogate individual kinase activities on substrates considering the confidence of the experimental versus the control groups using the equation: [Log2 Fold Change (FC) of kinase substrates ∗ Δconfidence (experimental hits/mean hits of 2000 random sampling iterations)]. Data input files for STK runs available on the GitHub repository at the following ( https://github.com/The-Hinds-Lab/Liver-Specific-Cpt1a-KO-Kinome-Analysis ).…”

Uridine diphosphate glucuronosyltransferase 1A1 prevents the progression of liver injury

“…Current research indicates that UGT1A1 mutation is a benign condition with no significant pathological response, and will not lead to hepatocyte death or chronic liver disease[ 4 ]. Moderate levels of bilirubin are effective physiological antioxidants[ 5 ], and may reduce oxidative stress, alleviate inflammation, prevent fibrosis, and ultimately affect the development of non-alcoholic fatty liver disease[ 6 , 7 ]. Furthermore, elevated levels of bilirubin can inhibit lipid oxidation and delay the development of atherosclerosis, thereby helping to prevent and counteract cardiovascular diseases such as coronary heart disease[ 8 ].…”