bims-liverm 2023-01-15 papers

Issue of 2023–01–15
four papers selected by

World J Gastroenterol. 2022 Dec 28. 28(48): 6846-6866

Bile acids and microbes in metabolic disease.

Dhiraj Kumar Sah, Archana Arjunan, Sun Young Park, Young Do Jung.

Bile acids (BAs) serve as physiological detergents that enable the intestinal absorption and transportation of nutrients, lipids and vitamins. BAs are primarily produced by humans to catabolize cholesterol and play crucial roles in gut metabolism, microbiota habitat regulation and cell signaling. BA-activated nuclear receptors regulate the enterohepatic circulation of BAs which play a role in energy, lipid, glucose, and drug metabolism. The gut microbiota plays an essential role in the biotransformation of BAs and regulates BAs composition and metabolism. Therefore, altered gut microbial and BAs activity can affect human metabolism and thus result in the alteration of metabolic pathways and the occurrence of metabolic diseases/syndromes, such as diabetes mellitus, obesity/hypercholesterolemia, and cardiovascular diseases. BAs and their metabolites are used to treat altered gut microbiota and metabolic diseases. This review explores the increasing body of evidence that links alterations of gut microbial activity and BAs with the pathogenesis of metabolic diseases. Moreover, we summarize existing research on gut microbes and BAs in relation to intracellular pathways pertinent to metabolic disorders. Finally, we discuss how therapeutic interventions using BAs can facilitate microbiome functioning and ease metabolic diseases.

Keywords: Bile acids; Diabetic mellitus; Gut microbe; Hypercholesterolemia; Metabolic diseases; Obesity

DOI: https://doi.org/10.3748/wjg.v28.i48.6846

Cell Biosci. 2023 Jan 09. 13(1): 5

Knockout of secretin ameliorates biliary and liver phenotypes during alcohol-induced hepatotoxicity.

BACKGROUND: Alcohol-related liver disease (ALD) is characterized by ductular reaction (DR), liver inflammation, steatosis, fibrosis, and cirrhosis. The secretin (Sct)/secretin receptor (SR) axis (expressed only by cholangiocytes) regulates liver phenotypes in cholestasis. We evaluated the role of Sct signaling on ALD phenotypes.
METHODS: We used male wild-type and Sct-/- mice fed a control diet (CD) or ethanol (EtOH) for 8 wk. Changes in liver phenotypes were measured in mice, female/male healthy controls, and patients with alcoholic cirrhosis. Since Cyp4a10 and Cyp4a11/22 regulate EtOH liver metabolism, we measured their expression in mouse/human liver. We evaluated: (i) the immunoreactivity of the lipogenesis enzyme elongation of very-long-chain fatty acids 1 (Elovl, mainly expressed by hepatocytes) in mouse/human liver sections by immunostaining; (ii) the expression of miR-125b (that is downregulated in cholestasis by Sct) in mouse liver by qPCR; and (iii) total bile acid (BA) levels in mouse liver by enzymatic assay, and the mRNA expression of genes regulating BA synthesis (cholesterol 7a-hydroxylase, Cyp27a1, 12a-hydroxylase, Cyp8b1, and oxysterol 7a-hydroxylase, Cyp7b11) and transport (bile salt export pump, Bsep, Na+-taurocholate cotransporting polypeptide, NTCP, and the organic solute transporter alpha (OSTa) in mouse liver by qPCR.
RESULTS: In EtOH-fed WT mice there was increased biliary and liver damage compared to control mice, but decreased miR-125b expression, phenotypes that were blunted in EtOH-fed Sct-/- mice. The expression of Cyp4a10 increased in cholangiocytes and hepatocytes from EtOH-fed WT compared to control mice but decreased in EtOH-fed Sct-/- mice. There was increased immunoreactivity of Cyp4a11/22 in patients with alcoholic cirrhosis compared to controls. The expression of miR-125b decreased in EtOH-fed WT mice but returned at normal values in EtOH-fed Sct-/- mice. Elovl1 immunoreactivity increased in patients with alcoholic cirrhosis compared to controls. There was no difference in BA levels between WT mice fed CD or EtOH; BA levels decreased in EtOH-fed Sct-/- compared to EtOH-fed WT mice. There was increased expression of Cyp27a1, Cyp8b1, Cyp7b1, Bsep, NTCP and Osta in total liver from EtOH-fed WT compared to control mice, which decreased in EtOH-fed Sct-/- compared to EtOH-fed WT mice.
CONCLUSIONS: Targeting Sct/SR signaling may be important for modulating ALD phenotypes.

Keywords: Biliary senescence; Ductular reaction; Fatty liver diseases; Hepatic steatosis; Lipogenesis

DOI: https://doi.org/10.1186/s13578-022-00945-w

Am J Physiol Regul Integr Comp Physiol. 2023 Jan 09.

Impact of sex and diet-induced weight loss on vascular insulin sensitivity in type 2 diabetes.

Camila Manrique-Acevedo, Rogerio Nogueira Soares, James A Smith, Lauren K Park, Katherine Burr, Francisco I Ramirez-Perez, Neil J McMillan, Larissa Ferreira-Santos, Neekun Sharma, T Dylan Olver, Craig A Emter, Elizabeth J Parks, Jacqueline K Limberg, Luis A Martinez-Lemus, Jaume Padilla.

Vascular insulin resistance, a major characteristic of obesity and type 2 diabetes (T2D), manifests with blunting of insulin-induced vasodilation. While there is evidence that females are more whole-body insulin sensitive than males in the healthy state, whether sex differences exist in vascular insulin sensitivity is unclear. Also uncertain is whether weight loss can reestablish vascular insulin sensitivity in T2D. The purpose of this investigation was to: 1) establish if sex differences in vasodilatory responses to insulin exist in absence of disease; 2) determine if female sex affords protection against the development of vascular insulin resistance with long-term overnutrition and obesity; and 3) examine if diet-induced weight loss can restore vascular insulin sensitivity in men and women with T2D. First, we show in healthy mice and humans that sex does not influence insulin-induced femoral artery dilation and insulin-stimulated leg blood flow, respectively. Second, we provide evidence that female mice are protected against impairments in insulin-induced dilation caused by overnutrition-induced obesity. Third, we show that men and women exhibit comparable levels of vascular insulin resistance when T2D develops, but that diet-induced weight loss is effective at improving insulin-stimulated leg blood flow, particularly in women. Lastly, we provide indirect evidence that these beneficial effects of weight loss may be mediated by a reduction in endothelin-1. In aggregate, the present data indicate that female sex confers protection against obesity-induced vascular insulin resistance and provide supportive evidence that, in women with T2D, vascular insulin resistance can be remediated with diet-induced weight loss.

Keywords: Vascular insulin resistance; obesity; sex differences; type 2 diabetes; vascular function

DOI: https://doi.org/10.1152/ajpregu.00249.2022

iScience. 2023 Jan 20. 26(1): 105802

Mapping transcriptional heterogeneity and metabolic networks in fatty livers at single-cell resolution.

Laetitia Coassolo, Tianyun Liu, Yunshin Jung, Nikki P Taylor, Meng Zhao, Gregory W Charville, Silas Boye Nissen, Hannele Yki-Jarvinen, Russ B Altman, Katrin J Svensson.

Non-alcoholic fatty liver disease is a heterogeneous disease with unclear underlying molecular mechanisms. Here, we perform single-cell RNA sequencing of hepatocytes and hepatic non-parenchymal cells to map the lipid signatures in mice with non-alcoholic fatty liver disease (NAFLD). We uncover previously unidentified clusters of hepatocytes characterized by either high or low srebp1 expression. Surprisingly, the canonical lipid synthesis driver Srebp1 is not predictive of hepatic lipid accumulation, suggestive of other drivers of lipid metabolism. By combining transcriptional data at single-cell resolution with computational network analyses, we find that NAFLD is associated with high constitutive androstane receptor (CAR) expression. Mechanistically, CAR interacts with four functional modules: cholesterol homeostasis, bile acid metabolism, fatty acid metabolism, and estrogen response. Nuclear expression of CAR positively correlates with steatohepatitis in human livers. These findings demonstrate significant cellular differences in lipid signatures and identify functional networks linked to hepatic steatosis in mice and humans.

Keywords: Molecular network; Molecular physiology; Systems biology; Transcriptomics

DOI: https://doi.org/10.1016/j.isci.2022.105802