bims-liverm 2023-01-01 papers

Issue of 2023‒01‒01
six papers selected by
Marti Cadena Sandoval
Columbia University

Front Immunol. 2022 ;13 1021924

Bile acids as inflammatory mediators and modulators of intestinal permeability.

Nathan Calzadilla, Shane M Comiskey, Pradeep K Dudeja, Seema Saksena, Ravinder K Gill, Waddah A Alrefai.

Bile acids are critical for the digestion and absorption of lipids and fat-soluble vitamins; however, evidence continues to emerge supporting additional roles for bile acids as signaling molecules. After they are synthesized from cholesterol in the liver, primary bile acids are modified into secondary bile acids by gut flora contributing to a diverse pool and making the composition of bile acids highly sensitive to alterations in gut microbiota. Disturbances in bile acid homeostasis have been observed in patients with Inflammatory Bowel Diseases (IBD). In fact, a decrease in secondary bile acids was shown to occur because of IBD-associated dysbiosis. Further, the increase in luminal bile acids due to malabsorption in Crohn's ileitis and ileal resection has been implicated in the induction of diarrhea and the exacerbation of inflammation. A causal link between bile acid signaling and intestinal inflammation has been recently suggested. With respect to potential mechanisms related to bile acids and IBD, several studies have provided strong evidence for direct effects of bile acids on intestinal permeability in porcine and rodent models as well as in humans. Interestingly, different bile acids were shown to exert distinct effects on the inflammatory response and intestinal permeability that require careful consideration. Such findings revealed a potential effect for changes in the relative abundance of different bile acids on the induction of inflammation by bile acids and the development of IBD. This review summarizes current knowledge about the roles for bile acids as inflammatory mediators and modulators of intestinal permeability mainly in the context of inflammatory bowel diseases.

Keywords: Crohn’s disease; bile acid receptors; bile acids; intestinal epithelial tight junction proteins; ulcerative

DOI: https://doi.org/10.3389/fimmu.2022.1021924

Prog Lipid Res. 2022 Dec 25. pii: S0163-7827(22)00065-0. [Epub ahead of print] 101210

Bile acids and their receptors in regulation of gut health and diseases.

Sen Lin, Sutian Wang, Peng Wang, Cuiming Tang, Zhenjiang Wang, Lian Chen, Guoqing Luo, Hong Chen, Yuntao Liu, Bin Feng, De Wu, Douglas G Burrin, Zhengfeng Fang.

It is well established that bile acids play important roles in lipid metabolism. In recent decades, bile acids have also been shown to function as signaling molecules via interacting with various receptors. Bile acids circulate continuously through the enterohepatic circulation and go through microbial transformation by gut microbes, and thus bile acids metabolism has profound effects on the liver and intestinal tissues as well as the gut microbiota. Farnesoid X receptor and G protein-coupled bile acid receptor 1 are two pivotal bile acid receptors that highly expressed in the intestinal tissues, and they have emerged as pivotal regulators in bile acids metabolism, innate immunity and inflammatory responses. There is considerable interest in manipulating the metabolism of bile acids and the expression of bile acid receptors as this may be a promising strategy to regulate intestinal health and disease. This review aims to summarize the roles of bile acids and their receptors in regulation of gut health and diseases.

Keywords: Bile acids; Colorectal cancers; FXR; GPBAR1; Inflammatory bowel diseases

DOI: https://doi.org/10.1016/j.plipres.2022.101210

PLoS One. 2022 ;17(12): e0279560

Loss of Slc12a2 specifically in pancreatic β-cells drives metabolic syndrome in mice.

Rana Abdelgawad, Yakshkumar Dilipbhai Rathod, Modhi Alshammari, Lisa Kelly, Christian A Hübner, Lydia Aguilar-Bryan, Mauricio Di Fulvio.

The risk of type-2 diabetes and cardiovascular disease is higher in subjects with metabolic syndrome, a cluster of clinical conditions characterized by obesity, impaired glucose metabolism, hyperinsulinemia, hyperlipidemia and hypertension. Diuretics are frequently used to treat hypertension in these patients, however, their use has long been associated with poor metabolic outcomes which cannot be fully explained by their diuretic effects. Here, we show that mice lacking the diuretic-sensitive Na+K+2Cl-cotransporter-1 Nkcc1 (Slc12a2) in insulin-secreting β-cells of the pancreatic islet (Nkcc1βKO) have reduced in vitro insulin responses to glucose. This is associated with islet hypoplasia at the expense of fewer and smaller β-cells. Remarkably, Nkcc1βKO mice excessively gain weight and progressive metabolic syndrome when fed a standard chow diet ad libitum. This is characterized by impaired hepatic insulin receptor activation and altered lipid metabolism. Indeed, overweight Nkcc1βKO but not lean mice had fasting and fed hyperglycemia, hypertriglyceridemia and non-alcoholic steatohepatitis. Notably, fasting hyperinsulinemia was detected earlier than hyperglycemia, insulin resistance, glucose intolerance and increased hepatic de novo gluconeogenesis. Therefore, our data provide evidence supporting the novel hypothesis that primary β-cell defects related to Nkcc1-regulated intracellular Cl-homeostasis and β-cell growth can result in the development of metabolic syndrome shedding light into additional potential mechanisms whereby chronic diuretic use may have adverse effects on metabolic homeostasis in susceptible individuals.

DOI: https://doi.org/10.1371/journal.pone.0279560

Liver Int. 2022 Dec 28.

Circadian rhythms and the liver.

Rodolfo Costa, Chiara Mangini, Esther Domenie, Lisa Zarantonello, Sara Montagnese.

This narrative review briefly describes the mammalian circadian timing system, the specific features of the liver clock, also by comparison with other peripheral clocks, the role of the liver clock in the preparation to food intake, and its relationship with energy metabolism. It then goes on to provide a chronobiological perspective of the pathophysiology and management of several types of liver disease, with particular focus on metabolic-associated fatty liver disease (MAFLD), decompensated cirrhosis and liver transplantation. Finally, it provides some insight into the potential contribution of circadian principles and circadian hygiene practices in preventing MAFLD, improving the prognosis of advanced liver disease and modulating liver transplantation outcomes.

DOI: https://doi.org/10.1111/liv.15501

Heliyon. 2022 Dec;8(12): e12294

Excessive gluconeogenesis causes the hepatic insulin resistance paradox and its sequelae.

Arnold N Onyango.

Background: Hepatic insulin signaling suppresses gluconeogenesis but promotes de novo lipid synthesis. Paradoxically, hepatic insulin resistance (HIR) enhances both gluconeogenesis and de novo lipid synthesis. Elucidation of the etiology of this paradox, which participates in the pathogenesis of non-alcoholic fatty liver disease (NAFLD), cardiovascular disease, the metabolic syndrome and hepatocellular carcinoma, has not been fully achieved.Scope of review: This article briefly outlines the previously proposed hypotheses on the etiology of the HIR paradox. It then discusses literature consistent with an alternative hypothesis that excessive gluconeogenesis, the direct effect of HIR, is responsible for the aberrant lipogenesis. The mechanisms involved therein are explained, involving de novo synthesis of fructose and uric acid, promotion of glutamine anaplerosis, and induction of glucagon resistance. Thus, gluconeogenesis via lipogenesis promotes hepatic steatosis, a component of NAFLD, and dyslipidemia. Gluconeogenesis-centred mechanisms for the progression of NAFLD from simple steatosis to non-alcoholic steatohepatitis (NASH) and fibrosis are suggested. That NAFLD often precedes and predicts type 2 diabetes is explained by the ability of lipogenesis to cushion against blood glucose dysregulation in the earlier stages of NAFLD.
Major conclusions: HIR-induced excessive gluconeogenesis is a major cause of the HIR paradox and its sequelae. Such involvement of gluconeogenesis in lipid synthesis rationalizes the fact that several types of antidiabetic drugs ameliorate NAFLD. Thus, dietary, lifestyle and pharmacological targeting of HIR and hepatic gluconeogenesis may be a most viable approach for the prevention and management of the HIR-associated network of diseases.

Keywords: Endoplasmic reticulum stress; Hexosamine biosynthetic pathway; Polyol pathway; Reactive oxygen species; Reductive carboxylation; Reductive stress

DOI: https://doi.org/10.1016/j.heliyon.2022.e12294

J Biol Chem. 2022 Dec 26. pii: S0021-9258(22)01278-9. [Epub ahead of print] 102835

The tetraspanin transmembrane protein CD53 mediates dyslipidemia and integrates inflammatory and metabolic signaling in hepatocytes.

Cassandra B Higgins, Joshua A Adams, Matthew H Ward, Zev J Greenberg, Małgorzata Milewska, Jiameng Sun, Yiming Zhang, Luana Chiquetto Paracatu, Qian Dong, Samuel Ballentine, Weikai Li, Ilona Wandzik, Laura G Schuettpelz, Brian J DeBosch.

Tetraspanins are transmembrane signaling and pro-inflammatory proteins. Prior work demonstrates the tetraspanin, CD53/TSPAN25/MOX44 mediates B-cell development, and lymphocyte homing and migration to lymph nodes, and is implicated in various inflammatory diseases including atherosclerosis and microbial infection. However, CD53 is also expressed in highly metabolic tissues, including adipose and liver, yet its function outside of the lymphoid compartment is not defined. Here, we show that CD53 demarcates the nutritional and inflammatory status of hepatocytes. High-fat exposure and inflammatory stimuli induced CD53 in vivo in liver and in isolated primary hepatocytes. In contrast, restricting hepatocyte glucose flux through hepatocyte GLUT8 deletion, or through trehalose treatment blocked CD53 induction in fat- and fructose-exposed contexts. Furthermore, germline CD53 deletion in vivo blocked western diet-induced dyslipidemia and hepatic inflammatory transcriptomic activation. Surprisingly, metabolic protection in CD53 KO mice was more pronounced in the presence of an inciting inflammatory event. CD53 deletion attenuated TNFα-induced and fatty acid + lipopolysaccharide-induced cytokine gene expression and hepatocyte triglyceride accumulation in isolated murine hepatocytes. In vivo, CD53 deletion in non-alcoholic steatohepatitis (NASH)-diet-fed mice blocked peripheral adipose accumulation and adipose inflammation, insulin tolerance, and liver lipid accumulation. We then define a stabilized, trehalase-resistant trehalose polymer that blocks hepatocyte CD53 expression in basal and over-fed contexts. The data suggest that CD53 integrates inflammatory and metabolic signals in response to hepatocyte nutritional status, and that CD53 blockade may be an effective means by which to attenuate pathophysiology in diseases that integrate overnutrition and inflammation, such as NASH and type 2 diabetes mellitus.

Keywords: CD53; FGF21; GLUT; MOX44 Liver; TSPAN25; Tetraspanin; arginase; autophagy; caloric restriction; diabetes; energy metabolism; fasting; glucose transport; insulin resistance; lactotrehalose; non-alcoholic fatty liver disease; obesity; polymers; proteomics; thermogenesis; trehalose

DOI: https://doi.org/10.1016/j.jbc.2022.102835