bims-liverm 2023-05-28 papers

Issue of 2023–05–28
seven papers selected by

J Lipid Res. 2023 May 19. pii: S0022-2275(23)00065-2. [Epub ahead of print] 100392

The Hylemon-Björkhem Pathway of Bile Acid 7-Dehydroxylation: History, Biochemistry, and Microbiology.

Jason M Ridlon, Steven L Daniel, H Rex Gaskins.

Bile acids are detergents derived from cholesterol that function to solubilize dietary lipids, remove cholesterol from the body, and act as nutrient signaling molecules in numerous tissues with functions in the liver and gut being the best understood. Studies in the early 20th century established the structures of bile acids, and by mid-century the application of gnotobiology to bile acids allowed differentiation of host-derived "primary" bile acids from "secondary bile acids" generated by host-associated microbiota. In 1960, radiolabeling studies in rodent models led to determination of the stereochemistry of the bile acid 7-dehydration reaction. A two-step mechanism was proposed, which we have termed the Samuelsson-Bergström model, to explain the formation of deoxycholic acid. Subsequent studies with humans, rodents, and cell extracts of Clostridium scindens VPI 12708 led to the realization that bile acid 7-dehydroxylation is a result of a multi-step, bifurcating pathway, that we have named the Hylemon-Björkhem Pathway. Due to the importance of hydrophobic secondary bile acids, and the increasing measurement of microbial bai genes encoding the enzymes that produce them in stool metagenome studies, it is important to understand their origin.

Keywords: allo-bile acids; bile acid dehydroxylation; bile acids; enterohepatic circulation; gut microbiome; intestinal lipid metabolism

DOI: https://doi.org/10.1016/j.jlr.2023.100392

J Lipid Res. 2023 May 18. pii: S0022-2275(23)00063-9. [Epub ahead of print] 100390

Circadian PER1 Controls Daily Fat Absorption with the Regulation of PER1-PKA on Phosphorylation of Bile Acid Synthetase.

Wenhao Ge, Qi Sun, Yunxia Yang, Zhao Ding, Junhao Liu, Jianfa Zhang.

Several epidemiological studies suggest a correlation between eating time and obesity. Night-eating syndrome characterized by a time-delayed eating pattern is positively associated with obesity in humans as well as in experimental animals. Here we show that oil intake at night significantly makes more fat than that at day in wild type (WT) mice, and circadian Period 1 (Per1) contributes to this day-night difference. Per1-knockout mice are protected from high-fat diet (HFD)-induced obesity, which is accompanied by a reduction in the size of the bile acid pool, and the oral administration of bile acids restores fat absorption and accumulation. We identify that PER1 directly binds to the major hepatic enzymes involved in bile acid synthesis such as cholesterol 7alpha-hydroxylase (CYP7A1) and sterol 12alpha-hydroxylase (CYP8B1). A biosynthesis rhythm of bile acids is accompanied by the activity and instability of bile acid synthases with PER1/PKA-mediated phosphorylation pathways. Both fasting and high fat stress enhance Per1 expression, increasing the fat absorption and accumulation. Our findings reveal that Per1 is an energy regulator and controls daily fat absorption and accumulation.

Keywords: Per1, Bile acid and salts/Bosynthesis; bile acid and salts; cholesterol 7-alpha hydroxylase; dietary fat; protein kinases

DOI: https://doi.org/10.1016/j.jlr.2023.100390

Membranes (Basel). 2023 Apr 28. pii: 472. [Epub ahead of print]13(5):

Bile Acids as Inducers of Protonophore and Ionophore Permeability of Biological and Artificial Membranes.

Victor N Samartsev, Ekaterina I Khoroshavina, Evgeniya K Pavlova, Mikhail V Dubinin, Alena A Semenova.

It is now generally accepted that the role of bile acids in the organism is not limited to their participation in the process of food digestion. Indeed, bile acids are signaling molecules and being amphiphilic compounds, are also capable of modifying the properties of cell membranes and their organelles. This review is devoted to the analysis of data on the interaction of bile acids with biological and artificial membranes, in particular, their protonophore and ionophore effects. The effects of bile acids were analyzed depending on their physicochemical properties: namely the structure of their molecules, indicators of the hydrophobic-hydrophilic balance, and the critical micelle concentration. Particular attention is paid to the interaction of bile acids with the powerhouse of cells, the mitochondria. It is of note that bile acids, in addition to their protonophore and ionophore actions, can also induce Ca2+-dependent nonspecific permeability of the inner mitochondrial membrane. We consider the unique action of ursodeoxycholic acid as an inducer of potassium conductivity of the inner mitochondrial membrane. We also discuss a possible relationship between this K+ ionophore action of ursodeoxycholic acid and its therapeutic effects.

Keywords: bile acids; ionophore; liver; membranes; mitochondria; nonspecific permeability; protonophore

DOI: https://doi.org/10.3390/membranes13050472

Biochim Biophys Acta Mol Cell Biol Lipids. 2023 May 22. pii: S1388-1981(23)00057-4. [Epub ahead of print] 159333

Hepatic deletion of serine palmitoyl transferase 2 impairs ceramide/sphingomyelin balance, bile acids homeostasis and leads to liver damage in mice.

Justine Lallement, Ilyès Raho, Grégory Merlen, Dominique Rainteau, Mikael Croyal, Melody Schiffano, Nadim Kassis, Isabelle Doignon, Maud Soty, Floriane Lachkar, Michel Krempf, Matthias Van Hul, Patrice D Cani, Fabienne Foufelle, Chloé Amouyal, Hervé Le Stunff, Christophe Magnan, Thierry Tordjmann, Céline Cruciani-Guglielmacci.

Ceramides (Cer) have been shown as lipotoxic inducers, which disturb numerous cell-signaling pathways, leading to metabolic disorders such as type 2 diabetes. In this study, we aimed to determine the role of de novo hepatic ceramide synthesis in energy and liver homeostasis in mice. We generated mice lacking serine palmitoyltransferase 2 (Sptlc2), the rate limiting enzyme of ceramide de novo synthesis, in liver under albumin promoter. Liver function, glucose homeostasis, bile acid (BA) metabolism and hepatic sphingolipids content were assessed using metabolic tests and LC-MS. Despite lower expression of hepatic Sptlc2, we observed an increased concentration of hepatic Cer, associated with a 10-fold increase in neutral sphingomyelinase 2 (nSMase2) expression, and a decreased sphingomyelin content in the liver. Sptlc2ΔLiv mice were protected against obesity induced by high fat diet and displayed a defect in lipid absorption. In addition, an important increase in tauro-muricholic acid was associated with a downregulation of the nuclear BA receptor FXR target genes. Sptlc2 deficiency also enhanced glucose tolerance and attenuated hepatic glucose production, while the latter effect was dampened in presence of nSMase2 inhibitor. Finally, Sptlc2 disruption promoted apoptosis, inflammation and progressive development of hepatic fibrosis, worsening with age. Our data suggest a compensatory mechanism to regulate hepatic ceramides content from sphingomyelin hydrolysis, with deleterious impact on liver homeostasis. In addition, our results show the involvement of hepatic sphingolipid modulation in BA metabolism and hepatic glucose production in an insulin-independent manner, which highlight the still under-researched role of ceramides in many metabolic functions.

Keywords: Bile acids; Ceramides; Fibrosis; Gluconeogenesis; Liver; Sphingomyelinase

DOI: https://doi.org/10.1016/j.bbalip.2023.159333

J Hepatol. 2023 May 23. pii: S0168-8278(23)00341-0. [Epub ahead of print]

Roux-en-Y gastric bypass induces hepatic transcriptomic signatures and plasma metabolite changes indicative of improved cholesterol homeostasis.

BACKGROUND & AIMS: Roux-en-Y gastric bypass (RYGB), the most weight-loss effective surgical procedure, decreases obesity and comorbidities, such as non-alcoholic fatty liver (NAFLD) and cardiovascular (CVD) diseases. Cholesterol is a major CVD risk factor and modulator of NAFLD development, and the liver tightly controls its metabolism. How RYGB surgery modulates systemic and hepatic cholesterol metabolism is still unclear.
METHODS: We studied the hepatic transcriptome of 26 non-diabetic obese patients undergoing RYGB before and one-year post-surgery. In parallel, we measured quantitative changes in plasma cholesterol metabolites and bile acids (BA).
RESULTS: RYGB surgery improved systemic cholesterol metabolism and increased plasma total and primary BA levels. Transcriptomic analysis revealed specific alterations in the liver after RYGB, with the down-regulation of a module of genes implicated in inflammation and the up-regulation of three modules, one associated with BA metabolism. A dedicated analysis of hepatic genes related to cholesterol homeostasis pointed towards increased biliary cholesterol elimination after RYGB, associated with enhancement of the alternate, but not the classical, BA synthesis pathway. In parallel, alterations in the expression of genes involved in cholesterol uptake and intracellular trafficking indicate improved hepatic free cholesterol handling. Finally, RYGB decreased plasma markers of cholesterol synthesis, which correlated with post-surgery liver disease status improvement.
CONCLUSIONS: Our results identify specific regulatory effects of RYGB on inflammation and cholesterol metabolism. RYGB alters the hepatic transcriptome signature, likely improving liver cholesterol homeostasis. These gene regulatory effects are reflected by systemic post-surgery changes of cholesterol-related metabolites, corroborating the beneficial effects of RYGB on both hepatic and systemic cholesterol homeostasis.
IMPACTS AND IMPLICATION: Roux-en-Y gastric bypass (RYGB) is a widely used bariatric surgery procedure with proven efficacy in body weight management, combatting cardiovascular disease (CVD) and non-alcoholic fatty liver disease (NAFLD). RYGB exerts many beneficial metabolic effects, by lowering plasma cholesterol and improving atherogenic dyslipidemia. Using a cohort of RYGB patients, studied before and one year after surgery, we analyzed how RYGB modulates hepatic and systemic cholesterol and bile acid metabolism. The results of our study provide important insights on the regulation of cholesterol homeostasis after RYGB and open avenues that could guide future monitoring and treatment strategies targeting CVD and NAFLD in obesity.

Keywords: Roux-en-Y gastric bypass; bile acid; cholesterol; liver; transcriptome

DOI: https://doi.org/10.1016/j.jhep.2023.05.012

Nutrients. 2023 May 22. pii: 2411. [Epub ahead of print]15(10):

Crosstalk between Gut Microbiota and Bile Acids in Cholestatic Liver Disease.

Qingmiao Shi, Xin Yuan, Yifan Zeng, Jinzhi Wang, Yaqi Zhang, Chen Xue, Lanjuan Li.

Emerging evidence suggests the complex interactions between gut microbiota and bile acids, which are crucial end products of cholesterol metabolism. Cholestatic liver disease is characterized by dysfunction of bile production, secretion, and excretion, as well as excessive accumulation of potentially toxic bile acids. Given the importance of bile acid homeostasis, the complex mechanism of the bile acid-microbial network in cholestatic liver disease requires a thorough understanding. It is urgent to summarize the recent research progress in this field. In this review, we highlight how gut microbiota regulates bile acid metabolism, how bile acid pool shapes the bacterial community, and how their interactions contribute to the pathogenesis of cholestatic liver disease. These advances might provide a novel perspective for the development of potential therapeutic strategies that target the bile acid pathway.

Keywords: bile acid; cholestatic liver disease; crosstalk; gut microbiota

DOI: https://doi.org/10.3390/nu15102411

Lett Appl Microbiol. 2023 May 23. pii: ovad062. [Epub ahead of print]

Identification of genes essential for bile acid resistance in the probiotic Lacticaseibacillus paracasei strain Shirota.

Kensuke Shimizu, Masahiro Ito, Miyuki Katto, Toshihiko Takada, Kosuke Oana, Hiroshi Makino, Nobuhiko Okada, Takashi Kurakawa, Kenji Oishi.

Bile acid resistance is crucial to allow probiotic strains to survive in the gastrointestinal tract and exert health-promoting effects on their hosts. Our aim here was to determine the mechanism of this resistance via a genetic approach by identifying the genes essential for bile acid resistance in Lacticaseibacillus paracasei strain Shirota (LcS). We generated 4649 transposon-inserted lines of L. paracasei YIT 0291, which has the same genome sequence as LcS but lacks the pLY101 plasmid, and we screened them for bile-acid-sensitive mutants. The growth of 14 mutated strains was strongly inhibited by bile acid, and we identified 10 genes that could be involved in bile acid resistance. Expression of these genes was not markedly induced by bile acid, suggesting that their homeostatic expression is important for exerting bile acid resistance. Two mutants, in which the transposon was independently inserted into cardiolipin synthase genes, showed strong growth inhibition. Disruption of the cardiolipin synthase genes in LcS caused decreased cardiolipin production and accumulation of the precursor phosphatidylglycerol in bacterial cells. These data suggest that LcS possesses several mechanisms for exerting bile acid resistance, and that homeostatic cardiolipin production is among the factors most essential for this resistance.

Keywords: Lacticaseibacillus paracasei strain Shirota; bile acid; cardiolipin; transposon

DOI: https://doi.org/10.1093/lambio/ovad062