bims-liverm 2022-12-04 papers

bims-liverm

Biomed News

on Liver Metabolism

Issue of 2022–12–04
eleven papers selected by

Odevixibat: an investigational inhibitor of the ileal bile acid transporter (IBAT) for the treatment of biliary atresia.
Dietary bile acid supplementation alters plasma biochemical and hormone indicators, intestinal digestive capacity, and microbiota of piglets with normal birth weight and intrauterine growth retardation.
NUDT7 regulates total hepatic CoA levels and the composition of the intestinal bile acid pool in male mice fed a Western diet.
PPARγ (Peroxisome Proliferator-Activated Receptor γ) Deacetylation Suppresses Aging-Associated Atherosclerosis and Hypercholesterolemia.
The protective effects of sulforaphane on high-fat diet-induced metabolic associated fatty liver disease in mice via mediating the FXR/LXRα pathway.
Gut Microbiome and Metabolites, the Future Direction of Diagnosis and Treatment of Atherosclerosis?
Deletion of Jazf1 gene causes early growth retardation and insulin resistance in mice.
From Antiquity to Modern Times: A History of Diabetes Mellitus and Its Treatments.
G protein-coupled receptor 151 regulates glucose metabolism and hepatic gluconeogenesis.
Gut microbial DNA and immune checkpoint gene Vsig4/CRIg are key antagonistic players in healthy aging and age-associated development of hypertension and diabetes.
Design and synthesis of bile acid derivatives and their activity against colon cancer.

Expert Opin Investig Drugs. 2022 Nov 28.

Odevixibat: an investigational inhibitor of the ileal bile acid transporter (IBAT) for the treatment of biliary atresia.

Tobias Laue, Ulrich Baumann.

   INTRODUCTION: Biliary atresia (BA) is a rare, non-curable cholestasis-causing disease in infancy, due to progressive ascending bile duct sclerosis. Even after restoration of bile flow following Kasai portoenterostomy, about half of these children need a liver transplant by their 2nd birthday, due to progressive fibrosis. Toxicity of bile acids may play a central role in disease progression, but drug therapies are not yet available. With ileal bile acid transporter (IBAT) inhibitors, there is a potential novel drug option that inhibits the absorption of bile acids in the small intestine. As a result of reduced bile acid accumulation in the cholestatic liver, it may be possible to delay hepatic remodeling.
AREAS COVERED: This review summarizes the dataset on bile acids and the potential effects of odevixibat, an IBAT inhibitor, in children with BA.
EXPERT OPINION: Systemic reduction of bile acids with the aim of preventing inflammation, and thus liver remodeling, is a novel, promising, therapeutic concept. In principle, however, the time until diagnosis and surgical treatment of BA should still be kept as short as possible in order to minimize liver remodeling before medical intervention can be initiated. The new group of IBAT inhibitors may add to the medical options in limiting disease progression in BA.

Keywords:  Biliary atresia; IBAT; bile acids; children; ileal bile acid transporter; odevixibat

DOI:  https://doi.org/10.1080/13543784.2022.2151890
Front Microbiol. 2022 ;13 1053128

Dietary bile acid supplementation alters plasma biochemical and hormone indicators, intestinal digestive capacity, and microbiota of piglets with normal birth weight and intrauterine growth retardation.

Yang Liu, Md Abul Kalam Azad, Qian Zhu, Zugong Yu, Xiangfeng Kong.

  Piglets with intrauterine growth retardation (IUGR) have poor small intestinal morphology and function, resulting in impaired digestion and absorption of nutrients and lower growth performance. Bile acids (BA) are important in regulating digestive enzyme activity, digestion and absorption of lipids, intestinal development, and protecting the liver. The present study aimed to investigate the effects of dietary BA supplementation on plasma biochemical and hormone indicators, intestinal morphology and function, and microbial community in piglets with normal birth weight (NBW) and IUGR. Weaned piglets (24 IUGR and 24 NBW) were allocated to four groups (12 piglets per group) and fed the following diets: (i) NBW group, NBW piglets fed a basal diet; (ii) NBW + BA group, NBW piglets fed a basal diet with 400 mg/kg BA; (iii) IUGR group, IUGR piglets fed a basal diet; and (iv) IUGR + BA group, IUGR piglets fed a basal diet with 400 mg/kg BA. The feeding trial lasted 28 days. The results showed that IUGR decreased the weight of the jejunum, whereas dietary BA supplementation decreased the jejunum weight and increased the length, weight, and index of ileum in NBW piglets (p < 0.05). In addition, IUGR increased (p < 0.05) the plasma choline esterase (CHE) and glucose levels of weaned piglets regardless of BA supplementation. Dietary BA supplementation increased the plasma albumin, triglyceride, and total protein concentrations while decreased plasma aspartate transaminase (AST), alanine aminotransferase (ALT), CHE, lactate dehydrogenase, and NH3 levels regardless of IUGR (p < 0.05). The IUGR increased trypsin level in the ileum, whereas dietary BA supplementation decreased jejunal trypsin and lipase and ileal lipase levels of weaned piglets regardless of IUGR (p < 0.05). Spearman's correlation analysis revealed the potential link between the intestinal microbial community and intestinal health-related indices of weaned piglets. These findings suggest that IUGR could decrease small intestinal morphology and function, whereas dietary BA supplementation could promote the ileum development of NBW piglets, protect the liver by reducing plasma ALT and AST levels, and increase the proportion of potentially beneficial bacteria in the small intestine of NBW and IUGR piglets, contributing to intestinal development and health of weaned piglets.

Keywords:  bile acid; digestive capacity; intestinal development; intrauterine growth retardation; liver protection; microbial community; weaned piglet

DOI:  https://doi.org/10.3389/fmicb.2022.1053128
J Biol Chem. 2022 Nov 24. pii: S0021-9258(22)01188-7. [Epub ahead of print] 102745

NUDT7 regulates total hepatic CoA levels and the composition of the intestinal bile acid pool in male mice fed a Western diet.

Schuyler D Vickers, Stephanie A Shumar, Dominique C Saporito, Amina Kunovac, Quincy A Hathaway, Breeanna Mintmier, Judy A King, Rachel D King, Vazhaikkurichi M Rajendran, Aniello M Infante, John M Hollander, Roberta Leonardi.

  Nudix hydrolase 7 (NUDT7) is an enzyme that hydrolyzes CoA species, is highly expressed in the liver, and resides in the peroxisomes. Peroxisomes are organelles where the preferential oxidation of dicarboxylic fatty acids occurs and where the hepatic synthesis of the primary bile acids cholic acid and chenodeoxycholic acid is completed. We previously showed that liver-specific overexpression of NUDT7 affects peroxisomal lipid metabolism, but does not prevent the increase in total liver CoA levels that occurs during fasting. We generated Nudt7-/- mice to further characterize the role that peroxisomal (acyl-)CoA degradation plays in the modulation of the size and composition of the acyl-CoA pool and in the regulation of hepatic lipid metabolism. Here we show that deletion of Nudt7 alters the composition of the hepatic acyl-CoA pool in mice fed a low-fat diet, but only in males fed a Western diet does the lack of NUDT7 activity increase total liver CoA levels. This effect is driven by the male-specific accumulation of medium-chain dicarboxylic acyl-CoAs, which are produced from the β-oxidation of dicarboxylic fatty acids. We also show that, under conditions of elevated synthesis of chenodeoxycholic acid derivatives, Nudt7 deletion promotes the production of tauromuricholic acid, decreasing the hydrophobicity index of the intestinal bile acid pool and increasing fecal cholesterol excretion in male mice. These findings reveal that NUDT7-mediated hydrolysis of acyl-CoA pathway intermediates in liver peroxisomes contributes to the regulation of dicarboxylic fatty acid metabolism and the composition of the bile acid pool.

Keywords:  Nudix hydrolases; bile acids; cholesterol; dicarboxylic fatty acids; peroxisomes

DOI:  https://doi.org/10.1016/j.jbc.2022.102745
Arterioscler Thromb Vasc Biol. 2022 Dec 01.

PPARγ (Peroxisome Proliferator-Activated Receptor γ) Deacetylation Suppresses Aging-Associated Atherosclerosis and Hypercholesterolemia.

Tarik Zahr, Longhua Liu, Michelle Chan, Qiuzhong Zhou, Bishuang Cai, Ying He, Nicole Aaron, Domenico Accili, Lei Sun, Li Qiang.

   BACKGROUND: Atherosclerosis is a medical urgency manifesting at the onset of hypercholesterolemia and is associated with aging. Activation of PPARγ (peroxisome proliferator-activated receptor γ) counteracts metabolic dysfunction influenced by aging, and its deacetylation displays an atheroprotective property. Despite the marked increase of PPARγ acetylation during aging, it is unknown whether PPARγ acetylation is a pathogenic contributor to aging-associated atherosclerosis.
METHODS: Mice with constitutive deacetylation-mimetic PPARγ mutations on lysine residues K268 and K293 (2KR) in an LDL (low-density lipoprotein)-receptor knockout (Ldlr-/-) background (2KR:Ldlr-/-) were aged for 18 months on a standard laboratory diet to examine the cardiometabolic phenotype, which was confirmed in Western-type diet-fed 2KR:Ldlr+/- mice. Whole-liver RNA-sequencing and in vitro studies in bone marrow-derived macrophages were conducted to decipher the mechanism.
RESULTS: In contrast to severe atherosclerosis in WT:Ldlr-/- mice, aged 2KR:Ldlr-/- mice developed little to no plaque, which was underlain by a significantly improved plasma lipid profile, with particular reductions in circulating LDL. The protection from hypercholesterolemia was recapitulated in Western-type diet-fed 2KR:Ldlr+/- mice. Liver RNA-sequencing analysis revealed suppression of liver inflammation rather than changes in cholesterol metabolism. This anti-inflammatory effect of 2KR was attributed to polarized M2 activation of macrophages. Additionally, the upregulation of core circadian component Bmal1, perceived to be involved in anti-inflammatory immunity, was observed in the liver and bone marrow-derived macrophages.
CONCLUSIONS: PPARγ deacetylation in mice prevents the development of aging-associated atherosclerosis and hypercholesterolemia, in association with the anti-inflammatory phenotype of 2KR macrophages.

Keywords:  aging; atherosclerosis; cardiovascular disease; hypercholesterolemia; inflammation

DOI:  https://doi.org/10.1161/ATVBAHA.122.318061
Food Funct. 2022 Nov 30.

The protective effects of sulforaphane on high-fat diet-induced metabolic associated fatty liver disease in mice via mediating the FXR/LXRα pathway.

Shaotong Ma, Xinyi Pang, Shuhua Tian, Jing Sun, Qiaobin Hu, Xiangfei Li, Yingjian Lu.

Metabolic-associated fatty liver disease (MAFLD) is becoming the key factor in causing chronic liver disease all over the world. Sulforaphane (SFN) has been proven to be effective in alleviating many metabolic diseases, such as obesity and type 2 diabetes. In this study, C57BL/6 mice were fed a high-fat diet for 12 weeks to induce MAFLD and given SFN (10 mg per kg bw) daily. Our results showed that SFN not only improved the excessive accumulation of fat in the liver cells but also ameliorated liver and serum inflammatory and antioxidant levels. In addition, SFN can regulate bile-acid metabolism and fatty-acid synthesis by affecting their farnesoid X receptor (FXR)/liver X receptor alpha (LXRα) signaling pathway, ultimately alleviating MAFLD. Our study provides a theoretical basis for the mechanism by which SFN alleviates hepatic steatosis.

DOI: https://doi.org/10.1039/d2fo02341e
Pharmacol Res. 2022 Nov 29. pii: S1043-6618(22)00532-1. [Epub ahead of print] 106586

Gut Microbiome and Metabolites, the Future Direction of Diagnosis and Treatment of Atherosclerosis?

Huanhuan Cao, Yujie Zhu, Gaofei Hu, Qi Zhang, Lemin Zheng.

  Over the past few decades, the treatment of atherosclerotic cardiovascular disease has mainly been through an LDL lowering strategy and treatments targeting other traditional risk factors for atherosclerosis, which has significantly reduced cardiovascular mortality. However, the overall benefit of targeting these risk factors has stagnated, and the discovery of new therapeutic targets for atherosclerosis remains a challenge. Accumulating evidence from clinical and animal experiments has revealed that the gut microbiome play a significant role in human health and disease, including cardiovascular diseases. The gut microbiome contribute to host health and disease through microbial composition and function. The gut microbiome function like an endocrine organ by generating bioactive metabolites that can impact atherosclerosis. In this review, we describe two gut microbial metabolites/pathways by which the gut affects atherosclerotic cardiovascular disease. On the one hand, we discuss the effects of trimethylamine oxide (TMAO), bile acids and aromatic amino acid metabolites on the development of atherosclerosis, and the protective effects of beneficial metabolites short chain amino acids and polyamines on atherosclerosis. On the other hand, we discuss novel therapeutic strategies for directly targeting gut microbial metabolites to improve cardiovascular outcomes. Reducing gut-derived TMAO levels and interfering with the bile acid receptor farnesoid X receptor (FXR) are new therapeutic strategies for atherosclerotic disease. Enzymes and receptors in gut microbiota metabolic pathways are potential new drug targets. We need solid insight into these underlying mechanisms to pave the way for therapeutic strategies targeting gut microbial metabolites/pathways for atherosclerotic cardiovascular disease.

Keywords:  TMAO; atherosclerosis; bile acids; gut microbiome; metabolites

DOI:  https://doi.org/10.1016/j.phrs.2022.106586
Proc Natl Acad Sci U S A. 2022 Dec 06. 119(49): e2213628119

Deletion of Jazf1 gene causes early growth retardation and insulin resistance in mice.

Hui-Young Lee, Hye Rim Jang, Hui Li, Varman T Samuel, Karrie D Dudek, Anna B Osipovich, Mark A Magnuson, Jeffrey Sklar, Gerald I Shulman.

  Single-nucleotide polymorphisms in the human juxtaposed with another zinc finger protein 1 (JAZF1) gene have repeatedly been associated with both type 2 diabetes (T2D) and height in multiple genome-wide association studies (GWAS); however, the mechanism by which JAZF1 causes these traits is not yet known. To investigate the possible functional role of JAZF1 in growth and glucose metabolism in vivo, we generated Jazf1 knockout (KO) mice and examined body composition and insulin sensitivity both in young and adult mice by using 1H-nuclear magnetic resonance and hyperinsulinemic-euglycemic clamp techniques. Plasma concentrations of insulin-like growth factor 1 (IGF-1) were reduced in both young and adult Jazf1 KO mice, and young Jazf1 KO mice were shorter in stature than age-matched wild-type mice. Young Jazf1 KO mice manifested reduced fat mass, whereas adult Jazf1 KO mice manifested increased fat mass and reductions in lean body mass associated with increased plasma growth hormone (GH) concentrations. Adult Jazf1 KO manifested muscle insulin resistance that was further exacerbated by high-fat diet feeding. Gene set enrichment analysis in Jazf1 KO liver identified the hepatocyte hepatic nuclear factor 4 alpha (HNF4α), which was decreased in Jazf1 KO liver and in JAZF1 knockdown cells. Moreover, GH-induced IGF-1 expression was inhibited by JAZF1 knockdown in human hepatocytes. Taken together these results demonstrate that reduction of JAZF1 leads to early growth retardation and late onset insulin resistance in vivo which may be mediated through alterations in the GH-IGF-1 axis and HNF4α.

Keywords:  height; hnf4a; insulin like growth factor 1; jazf1; type 2 diabetes

DOI:  https://doi.org/10.1073/pnas.2213628119
Horm Res Paediatr. 2022 ;95(6): 593-607

From Antiquity to Modern Times: A History of Diabetes Mellitus and Its Treatments.

Christine A March, Ingrid M Libman, Dorothy J Becker, Lynne L Levitsky.

  The past 200 years have brought an understanding of diabetes and its pathogenesis, as well as the development of treatments that could not have been predicted when the disorder was first clinically described 2000 years ago. Beginning in the late 19th century, the initial descriptions of the microscopic anatomy of the pancreatic islets by Langerhans led to recognition of pancreatic endocrine function. Many investigators attempted to isolate the hypoglycemic factor produced by the pancreas, but Banting, Best, Macleod, and Collip were able to extract and purify "isletin" to treat human diabetes in 1921. Rapid scientific progress over the next 100 years led to an understanding of insulin synthesis, structure and function, production of modified synthetic insulins, and the physiopathology that permitted classification of diabetes subtypes. Improvements in control of diabetes have reduced the risks of complications. In less than two hundred years, we have gone from being unable to measure glucose in blood to being able to offer people with diabetes continuous blood glucose monitoring, linked to continuous subcutaneous insulin infusion. We come ever closer with new drugs and treatments to repair the biochemical defects in type 2 diabetes and to biologically replace islets and their function in type 1 diabetes. This review addresses the history of continuing progress in diabetes care.

Keywords:  History; Insulin; Insulin receptor; Type 1 diabetes; Type 2 diabetes

DOI:  https://doi.org/10.1159/000526441
Nat Commun. 2022 Dec 01. 13(1): 7408

G protein-coupled receptor 151 regulates glucose metabolism and hepatic gluconeogenesis.

Ewa Bielczyk-Maczynska, Meng Zhao, Peter-James H Zushin, Theresia M Schnurr, Hyun-Jung Kim, Jiehan Li, Pratima Nallagatla, Panjamaporn Sangwung, Chong Y Park, Cameron Cornn, Andreas Stahl, Katrin J Svensson, Joshua W Knowles.

Human genetics has been instrumental in identification of genetic variants linked to type 2 diabetes. Recently a rare, putative loss-of-function mutation in the orphan G-protein coupled receptor 151 (GPR151) was found to be associated with lower odds ratio for type 2 diabetes, but the mechanism behind this association has remained elusive. Here we show that Gpr151 is a fasting- and glucagon-responsive hepatic gene which regulates hepatic gluconeogenesis. Gpr151 ablation in mice leads to suppression of hepatic gluconeogenesis genes and reduced hepatic glucose production in response to pyruvate. Importantly, the restoration of hepatic Gpr151 levels in the Gpr151 knockout mice reverses the reduced hepatic glucose production. In this work, we establish a previously unknown role of Gpr151 in the liver that provides an explanation to the lowered type 2 diabetes risk in individuals with nonsynonymous mutations in GPR151.

DOI: https://doi.org/10.1038/s41467-022-35069-9
Front Endocrinol (Lausanne). 2022 ;13 1037465

Gut microbial DNA and immune checkpoint gene Vsig4/CRIg are key antagonistic players in healthy aging and age-associated development of hypertension and diabetes.

Matthew A Liu, Shandy Shahabi, Suborno Jati, Kechun Tang, Hong Gao, Zhongmou Jin, Wyatt Miller, Frédéric A Meunier, Wei Ying, Geert van den Bogaart, Gourisankar Ghosh, Sushil K Mahata.

   Aims: Aging is associated with the development of insulin resistance and hypertension which may stem from inflammation induced by accumulation of toxic bacterial DNA crossing the gut barrier. The aim of this study was to identify factors counter-regulating these processes. Taking advantage of the Chromogranin A (CgA) knockout (CgA-KO) mouse as a model for healthy aging, we have identified Vsig4 (V-set and immunoglobulin domain containing 4) as the critical checkpoint gene in offsetting age-associated hypertension and diabetes.
Methods and Results: The CgA-KO mice display two opposite aging phenotypes: hypertension but heightened insulin sensitivity at young age, whereas the blood pressure normalizes at older age and insulin sensitivity further improves. In comparison, aging WT mice gradually lost glucose tolerance and insulin sensitivity and developed hypertension. The gut barrier, compromised in aging WT mice, was preserved in CgA KO mice leading to major 35-fold protection against bacterial DNA-induced inflammation. Similarly, RNA sequencing showed increased expression of the Vsig4 gene (which removes bacterial DNA) in the liver of 2-yr-old CgA-KO mice, which may account for the very low accumulation of microbial DNA in the heart. The reversal of hypertension in aging CgA-KO mice likely stems from (i) low accumulation of microbial DNA, (ii) decreased spillover of norepinephrine in the heart and kidneys, and (iii) reduced inflammation.
Conclusion: We conclude that healthy aging relies on protection from bacterial DNA and the consequent low inflammation afforded by CgA-KO. Vsig4 also plays a crucial role in "healthy aging" by counteracting age-associated insulin resistance and hypertension.

Keywords:  Chromogranin A; catestatin; diabetes; healthy aging; hypertension; insulin resistance; pancreastatin

DOI:  https://doi.org/10.3389/fendo.2022.1037465
RSC Med Chem. 2022 Nov 16. 13(11): 1391-1409

Design and synthesis of bile acid derivatives and their activity against colon cancer.

Zongyuan Wang, Xin Qiang, Yijie Peng, Yanni Wang, Quanyi Zhao, Dian He.

Bile acids (BAs) containing both hydrophilic hydroxyl and carboxyl groups and hydrophobic methyl and steroid nuclei can promote the absorption of fat and other substances in the intestine, and they are synthesized by cholesterol in the liver and then returned to the liver through enteric liver circulation. Because there are many BA receptors on the cell membrane of colon tissues, BAs can improve the specific delivery and transport of medicines to colon tissues. Moreover, BAs have a certain anticancer and inflammation activity by themselves. Based on this theory, a series of BA derivatives against colon cancer including cholic acid (CA), chenodeoxycholic acid (CDCA), ursodeoxycholic acid (UDCA) and lithocholic acid (LCA) were designed and synthesized, and their antitumor activity was evaluated. For in vitro anti-tumor tests, all the compounds displayed cell proliferative inhibition to nine human malignant tumor cell lines to some degree, and in particular they showed stronger inhibition to the colon cancer cells than the other cell lines. Among them, four compounds (4, 5, 6, and 7) showed stronger activity than the other compounds as well as the positive control 5-FU against HCT116 cells, and their IC50 was between 21.32 μmol L-1 and 28.90 μmol L-1; cell clone formation and migration tests showed that they not only effectively inhibited the formation of HCT116 cell colonies, but also inhibited the HCT116 cell migration and invasion; moreover, they induced apoptosis, arrested the mitotic process at the G2/M phase of the cell cycle, reduced the mitochondrial membrane potential, increased the intracellular ROS levels, and reduced the expression of Bcl-2 and p-STAT3 in HCT 116 cells. In addition, they also displayed intermediate anti-inflammatory activity by inhibiting inflammatory mediators NO and downregulating TNF-α expression, which also is one of the causes of colon cancer. This suggests that they deserve to be further investigated as candidates for colon cancer treatment drugs.

DOI: https://doi.org/10.1039/d2md00220e