bims-liverm 2023-06-25 papers

Issue of 2023–06–25
four papers selected by

Cardiovasc Diabetol. 2023 Jun 22. 22(1): 144

Genetic deletion of hepatic NCOR1 protects from atherosclerosis by promoting alternative bile acid-metabolism and sterol excretion.

Martin Geiger, Sara Oppi, Stefanie Nusser-Stein, Sarah Costantino, Shafeeq Ahmed Mohammed, Era Gorica, Joanne A Hoogerland, Christian M Matter, Ana T Guillaumon, Frank Ruschitzka, Francesco Paneni, Maaike H Oosterveer, Sokrates Stein.

BACKGROUND: The nuclear receptor corepressor 1 (NCOR1) plays an important role in the regulation of gene expression in immunometabolic conditions by connecting chromatin-modifying enzymes, coregulators and transcription factors. NCOR1 has been shown to be involved in cardiometabolic diseases. Recently, we demonstrated that the deletion of macrophage NCOR1 aggravates atherosclerosis by promoting CD36-triggered foam cell formation via PPARG derepression.
PURPOSE: Since NCOR1 modulates the function of several key regulators involved in hepatic lipid and bile acid metabolism, we hypothesized that its deletion in hepatocytes alters lipid metabolism and atherogenesis.
METHODS: To test this hypothesis, we generated hepatocyte-specific Ncor1 knockout mice on a Ldlr-/- background. Besides assessing the progression of the disease in thoracoabdominal aortae en face, we analyzed hepatic cholesterol and bile acid metabolism at expression and functional levels.
RESULTS: Our data demonstrate that liver-specific Ncor1 knockout mice on an atherosclerosis-prone background develop less atherosclerotic lesions than controls. Interestingly, under chow diet, plasma cholesterol levels of liver-specific Ncor1 knockout mice were slightly higher compared to control, but strongly reduced compared to control mice after feeding them an atherogenic diet for 12 weeks. Moreover, the hepatic cholesterol content was decreased in liver-specific Ncor1 knockout compared to control mice. Our mechanistic data revealed that NCOR1 reprograms the synthesis of bile acids towards the alternative pathway, which in turn reduce bile hydrophobicity and enhances fecal cholesterol excretion.
CONCLUSIONS: Our data suggest that hepatic Ncor1 deletion in mice decreases atherosclerosis development by reprograming bile acid metabolism and enhancing fecal cholesterol excretion.

Keywords: Atherosclerosis; Immunometabolic disease; Mechanism of disease; Ncor1; Nuclear receptor corepressor

DOI: https://doi.org/10.1186/s12933-023-01865-w

Nat Commun. 2023 Jun 20. 14(1): 3669

Gut microbiota Turicibacter strains differentially modify bile acids and host lipids.

Jonathan B Lynch, Erika L Gonzalez, Kayli Choy, Kym F Faull, Talia Jewell, Abelardo Arellano, Jennifer Liang, Kristie B Yu, Jorge Paramo, Elaine Y Hsiao.

Bacteria from the Turicibacter genus are prominent members of the mammalian gut microbiota and correlate with alterations in dietary fat and body weight, but the specific connections between these symbionts and host physiology are poorly understood. To address this knowledge gap, we characterize a diverse set of mouse- and human-derived Turicibacter isolates, and find they group into clades that differ in their transformations of specific bile acids. We identify Turicibacter bile salt hydrolases that confer strain-specific differences in bile deconjugation. Using male and female gnotobiotic mice, we find colonization with individual Turicibacter strains leads to changes in host bile acid profiles, generally aligning with those produced in vitro. Further, colonizing mice with another bacterium exogenously expressing bile-modifying genes from Turicibacter strains decreases serum cholesterol, triglycerides, and adipose tissue mass. This identifies genes that enable Turicibacter strains to modify host bile acids and lipid metabolism, and positions Turicibacter bacteria as modulators of host fat biology.

DOI: https://doi.org/10.1038/s41467-023-39403-7

J Biol Chem. 2023 Jun 20. pii: S0021-9258(23)01974-9. [Epub ahead of print] 104946

Transgenic mice lacking FGF15/19-SHP phosphorylation display altered bile acids and gut bacteria, promoting nonalcoholic fatty liver disease.

Young-Chae Kim, Ming Qi, Xingchen Dong, Sunmi Seok, Hao Sun, Byron Kemper, Ting Fu, Jongsook Kim Kemper.

Dysregulated bile acid (BA)/lipid metabolism and gut bacteria dysbiosis are tightly associated with development of obesity and non-alcoholic fatty liver disease (NAFLD). The orphan nuclear receptor, Small Heterodimer Partner (SHP/NR0B2), is a key regulator of BA/lipid metabolism, and its gene-regulating function is markedly enhanced by phosphorylation at Thr-58 mediated by a gut hormone, fibroblast growth factor-15/19 (FGF15/19). To investigate the role of this phosphorylation in whole-body energy metabolism, we generated transgenic SHP-T58A knock-in mice. Compared with wild-type (WT) mice, the phosphorylation-defective SHP-T58A mice gained weight more rapidly with decreased energy expenditure and increased lipid/BA levels. This obesity-prone phenotype was associated with upregulation of lipid/BA synthesis genes and downregulation of lipophagy/β-oxidation genes. Mechanistically, defective SHP phosphorylation selectively impaired its interaction with LRH-1, resulting in de-repression of SHP/LRH-1 target BA/lipid synthesis genes. Remarkably, BA composition and selective gut bacteria that are known to impact obesity, were also altered in these mice. Upon feeding a high fat diet, fatty liver developed more severely in SHP-T58A mice compared to WT mice. Treatment with antibiotics substantially improved the fatty liver phenotypes in both groups but had greater effects in the T58A mice so that the difference between the groups was largely eliminated. These results demonstrate that defective phosphorylation at a single nuclear receptor residue can impact whole-body energy metabolism by altering BA/lipid metabolism and gut bacteria, promoting complex metabolic disorders like NAFLD. Since posttranslational modifications generally act in gene- and context-specific manners, the FGF15/19-SHP phosphorylation axis may allow more targeted therapy for NAFLD.

Keywords: FXR; NAFLD; bile acid composition; gut microbiota; lipid metabolism; lipophagy

DOI: https://doi.org/10.1016/j.jbc.2023.104946

Ren Fail. 2023 Dec;45(1): 2226221

The relationship between bile acids levels and the prognosis of patients with diabetes on maintenance hemodialysis: a retrospective study.

Bin Li, Cong Peng, Yili Wang, Rong Ma, Ya Feng.

OBJECTIVE: There is a paucity of research on the association between bile acids (BAs) levels and all-cause death in patients with diabetes mellitus (DM) on maintenance hemodialysis (MHD). This study aimed to investigate the clinical characteristics of patients with DM on MHD according to different BAs levels and their impact on prognosis.
METHODS: A retrospective cohort of 1,081 patients on hemodialysis at Xindu People's Hospital and the First Affiliated Hospital of Chengdu Medical College were enrolled. Demographic and clinical characteristics were collected. The relationship between BAs and all-cause death risk was fitted using restricted cubic splines (RCS), and the BAs cutoff value was calculated. Patients were divided into low and high BAs groups based on the cutoff value. The primary endpoint was all-cause death and the secondary outcomes were deaths from cardiovascular events.
RESULTS: Finally, 387 patients with DM on MHD were included. The median BAs level of all patients was 4.0 μmol/L. The RCS-based BAs cutoff value was 3.5 μmol/L. The BAs levels correlated negatively with total cholesterol, low-density lipoprotein, and blood calcium levels. During the follow-up, 21.7% of the patients died. The multivariate Cox regression analysis demonstrated that patients with DM on MHD with higher BAs were associated independently with a decreased risk of all-cause death (HR =0.55; 95% CI, 0.35-0.81, p = 0.01) compared to those with lower BAs levels.
CONCLUSIONS: Higher BAs levels were associated with lower lipid levels in patients with DM on MHD. BAs is an independent risk factor for all-cause death in patients with DM on MHD.

Keywords: All-cause death; bile acid; diabetes mellitus; glycolipid metabolism; maintenance hemodialysis; prognosis; risk factors

DOI: https://doi.org/10.1080/0886022X.2023.2226221