bims-liverm 2022-11-20 papers

Issue of 2022–11–20
six papers selected by

Pharmacol Ther. 2022 Nov 15. pii: S0163-7258(22)00205-4. [Epub ahead of print] 108311

Michael J Hurley, Rachel Bates, Jane Macnaughtan, Anthony H V Schapira.

This review will focus on how bile acids are being used in clinical trials to treat neurological diseases due to their central involvement with the gut-liver-brain axis and their physiological and pathophysiological roles in both normal brain function and multiple neurological diseases. The synthesis of primary and secondary bile acids species and how the regulation of the bile acid pool may differ between the gut and brain is discussed. The expression of several bile acid receptors in brain and their currently known functions along with the tools available to manipulate them pharmacologically are examined, together with discussion of the interaction of bile acids with the gut microbiome and their lesser-known effects upon brain glucose and lipid metabolism. How dysregulation of the gut microbiome, aging and sex differences may lead to disruption of bile acid signalling and possible causal roles in a number of neurological disorders are also considered. Finally, we discuss how pharmacological treatments targeting bile acid receptors are currently being tested in an array of clinical trials for several different neurodegenerative diseases.

Keywords: Bile acids; Microbiome; Neurodegeneration; Parkinson's disease

DOI: https://doi.org/10.1016/j.pharmthera.2022.108311

Adv Sci (Weinh). 2022 Nov 17. e2204190

PPARγ Acetylation Orchestrates Adipose Plasticity and Metabolic Rhythms.

Ying He, Alana B'nai Taub, Lexiang Yu, Yifan Yao, Ruotong Zhang, Tarik Zahr, Nicole Aaron, Joseph LeSauter, Lihong Fan, Longhua Liu, Ruya Tazebay, Jianwen Que, Utpal Pajvani, Liheng Wang, Rae Silver, Li Qiang.

Systemic glucose metabolism and insulin activity oscillate in response to diurnal rhythms and nutrient availability with the necessary involvement of adipose tissue to maintain metabolic homeostasis. However, the adipose-intrinsic regulatory mechanism remains elusive. Here, the dynamics of PPARγ acetylation in adipose tissue are shown to orchestrate metabolic oscillation in daily rhythms. Acetylation of PPARγ displays a diurnal rhythm in young healthy mice, with the peak at zeitgeber time 0 (ZT0) and the trough at ZT18. This rhythmic pattern is deranged in pathological conditions such as obesity, aging, and circadian disruption. The adipocyte-specific acetylation-mimetic mutation of PPARγ K293Q (aKQ) restrains adipose plasticity during calorie restriction and diet-induced obesity, associated with proteolysis of a core circadian component BMAL1. Consistently, the rhythmicity in glucose tolerance and insulin sensitivity is altered in aKQ and the complementary PPARγ deacetylation-mimetic K268R/K293R (2KR) mouse models. Furthermore, the PPARγ acetylation-sensitive downstream target adipsin is revealed as a novel diurnal factor that destabilizes BMAL1 and mediates metabolic rhythms. These findings collectively signify that PPARγ acetylation is a hinge connecting adipose plasticity and metabolic rhythms, the two determinants of metabolic health.

Keywords: BMAL1; PPARγ acetylation; adipose plasticity; adipsin; metabolic rhythm

DOI: https://doi.org/10.1002/advs.202204190

Front Pharmacol. 2022 ;13 1027212

Bile acids-gut microbiota crosstalk contributes to the improvement of type 2 diabetes mellitus.

Ruolin Gao, Xiangjing Meng, Yili Xue, Min Mao, Yaru Liu, Xuewen Tian, Bo Sui, Xun Li, Pengyi Zhang.

Type 2 diabetes mellitus (T2DM) occurs that cannot effectively use the insulin. Insulin Resistance (IR) is a significant characteristic of T2DM which is also an essential treatment target in blood glucose regulation to prevent T2DM and its complications. Bile acids (BAs) are one group of bioactive metabolites synthesized from cholesterol in liver. BAs play an important role in mutualistic symbiosis between host and gut microbiota. It is shown that T2DM is associated with altered bile acid metabolism which can be regulated by gut microbiota. Simultaneously, BAs also reshape gut microbiota and improve IR and T2DM in the bidirectional communications of the gut-liver axis. This article reviewed the findings on the interaction between BAs and gut microbiota in improving T2DM, which focused on gut microbiota and its debinding function and BAs regulated gut microbiota through FXR/TGR5. Meanwhile, BAs and their derivatives that are effective for improving T2DM and other treatments based on bile acid metabolism were also summarized. This review highlighted that BAs play a critical role in the glucose metabolism and may serve as therapeutic targets in T2DM, providing a reference for discovering and screening novel therapeutic drugs.

Keywords: bile acids; enterohepatic cycling; gut microbiota; insulin sensitivity; type 2 diabetes mellitus

DOI: https://doi.org/10.3389/fphar.2022.1027212

Curr Opin Lipidol. 2022 Nov 14.

The feedback cycles between glucose, amino acids and lipids and alpha cell secretion and their role in metabolic fatty liver disease.

Marie Winther-Sørensen, Jens J Holst, Nicolai J Wewer Albrechtsen.

PURPOSE OF REVIEW: Glucagon increases hepatic glucose production and in patients with metabolic diseases, glucagon secretion is increased contributing to diabetic hyperglycemia. This review explores the role of amino acids and lipids in the regulation of glucagon secretion and how it may be disturbed in metabolic diseases such as obesity and metabolic associated fatty liver disease (MAFLD).
RECENT FINDINGS: Human and animal studies have shown that MAFLD is associated with glucagon resistance towards amino acid catabolism, resulting in elevated plasma levels of amino acids. A recent clinical study showed that MAFLD is also associated with glucagon resistance towards lipid metabolism. In contrast, MAFLD may not decrease hepatic sensitivity to the stimulatory effects of glucagon on glucose production.
SUMMARY: Elevated plasma levels of amino acids and lipids associated with MAFLD may cause diabetogenic hyperglucagonemia. MAFLD and glucagon resistance may therefore be causally linked to hyperglycemia and the development of type 2 diabetes.

DOI: https://doi.org/10.1097/MOL.0000000000000857

J Clin Endocrinol Metab. 2022 Nov 14. pii: dgac659. [Epub ahead of print]

Circulating bile acids as biomarkers for disease diagnosis and prevention.

Li Qi, Yongsheng Chen.

CONTEXT: Bile acids (BAs) are pivotal signalling molecules that regulate energy metabolism and inflammation. Recent epidemiological studies have reported specific alterations in circulating BA profiles in certain disease states, including obesity, type 2 diabetes mellitus, non-alcoholic fatty liver disease, and Alzheimer's disease. In the past decade, breakthroughs have been made regarding the translation of BA profiling into clinical use for disease prediction. In this review, we summarise and synthesise recent data on variation in circulating BA profiles in patients with various diseases to evaluate the value of these biomarkers in human plasma for early diagnosis.
EVIDENCE ACQUISITION: This review is based on a collection of primary and review literature gathered from a PubMed search for BAs, obesity, type 2 diabetes mellitus (T2DM), insulin resistance, non-alcoholic fatty liver disease (NAFLD), hepatocellular carcinoma (HCC), cholangiocarcinoma (CCA), colon cancer, and Alzheimer's disease (AD), among other keywords.
EVIDENCE SYNTHESIS: Subjects with obesity, T2DM, HCC, CCA, or AD showed specific alterations in circulating BA profiles. These alterations may have existed long before the initial diagnosis of the above diseases. The intricate relationship between obesity, IR, and NAFLD complicates the establishment of clear and independent associations between BA profiles and NASH. Alterations in the levels of TBAs and several BA species were seen across the entire spectrum of NAFLD, demonstrating significant increases with the worsening of histological features.
CONCLUSIONS: Aberrant circulating BA profiles are an early event in the onset and progression of obesity, T2DM, HCC, and AD. The pleiotropic effects of BAs explain these broad connections. Circulating BA profiles could provide a basis for the development of biomarkers for the diagnosis and prevention of a wide range of diseases.

Keywords: Alzheimer’s disease; bile acid; biomarker; hepatocellular carcinoma; non-alcoholic fatty liver disease; type 2 diabetes mellitus

DOI: https://doi.org/10.1210/clinem/dgac659

Proc Natl Acad Sci U S A. 2022 Nov 22. 119(47): e2206923119

PAHSAs reduce cellular senescence and protect pancreatic beta cells from metabolic stress through regulation of Mdm2/p53.

Maria F Rubin de Celis, Ruben Garcia-Martin, Ismail Syed, Jennifer Lee, Cristina Aguayo-Mazzucato, Susan Bonner-Weir, Barbara B Kahn.

Senescence in pancreatic beta cells plays a major role in beta cell dysfunction, which leads to impaired glucose homeostasis and diabetes. Therefore, prevention of beta cell senescence could reduce the risk of diabetes. Treatment of nonobese diabetic (NOD) mice, a model of type 1 autoimmune diabetes (T1D), with palmitic acid hydroxy stearic acids (PAHSAs), a novel class of endogenous lipids with antidiabetic and antiinflammatory effects, delays the onset and reduces the incidence of T1D from 82% with vehicle treatment to 35% with PAHSAs. Here, we show that a major mechanism by which PAHSAs protect islets of the NOD mice is by directly preventing and reversing the initial steps of metabolic stress-induced senescence. In vitro PAHSAs increased Mdm2 expression, which decreases the stability of p53, a key inducer of senescence-related genes. In addition, PAHSAs enhanced expression of protective genes, such as those regulating DNA repair and glutathione metabolism and promoting autophagy. We demonstrate the translational relevance by showing that PAHSAs prevent and reverse early stages of senescence in metabolically stressed human islets by the same Mdm2 mechanism. Thus, a major mechanism for the dramatic effect of PAHSAs in reducing the incidence of type 1 diabetes in NOD mice is decreasing cellular senescence; PAHSAs may have a similar benefit in humans.

Keywords: cellular senescence; diabetes; lipids; metabolic stress; pancreatic islets

DOI: https://doi.org/10.1073/pnas.2206923119