bims-nastce 2021-10-10 papers

bims-nastce

Biomed News

on NASH and T cells

Issue of 2021–10–10
nine papers selected by
Petra Hirsova, Mayo Clinic College of Medicine

CD73-mediated adenosine production by CD8 T cell-derived extracellular vesicles constitutes an intrinsic mechanism of immune suppression.
Rho-Kinase as a Therapeutic Target for Nonalcoholic Fatty Liver Diseases.
"Sweet death": Fructose as a metabolic toxin that targets the gut-liver axis.
Novel therapeutic targets for cholestatic and fatty liver disease.
Hepatic Lysosomal Acid Lipase Overexpression Worsens Hepatic Inflammation in Mice Fed a Western Diet.
Sex hormones regulate meta-inflammation in diet-induced obesity in mice.
Microbiota triggers STING-type I IFN-dependent monocyte reprogramming of the tumor microenvironment.
Molecular aspects of fructose metabolism and metabolic disease.
Multifaceted pathogenesis of liver steatosis in inflammatory bowel disease: a systematic review.

Nat Commun. 2021 Oct 08. 12(1): 5911

CD73-mediated adenosine production by CD8 T cell-derived extracellular vesicles constitutes an intrinsic mechanism of immune suppression.

Enja Schneider, Riekje Winzer, Anne Rissiek, Isabell Ricklefs, Catherine Meyer-Schwesinger, Franz L Ricklefs, Andreas Bauche, Jochen Behrends, Rudolph Reimer, Santra Brenna, Hauke Wasielewski, Melchior Lauten, Björn Rissiek, Berta Puig, Filippo Cortesi, Tim Magnus, Ralf Fliegert, Christa E Müller, Nicola Gagliani, Eva Tolosa.

Immune cells at sites of inflammation are continuously activated by local antigens and cytokines, and regulatory mechanisms must be enacted to control inflammation. The stepwise hydrolysis of extracellular ATP by ectonucleotidases CD39 and CD73 generates adenosine, a potent immune suppressor. Here we report that human effector CD8 T cells contribute to adenosine production by releasing CD73-containing extracellular vesicles upon activation. These extracellular vesicles have AMPase activity, and the resulting adenosine mediates immune suppression independently of regulatory T cells. In addition, we show that extracellular vesicles isolated from the synovial fluid of patients with juvenile idiopathic arthritis contribute to T cell suppression in a CD73-dependent manner. Our results suggest that the generation of adenosine upon T cell activation is an intrinsic mechanism of human effector T cells that complements regulatory T cell-mediated suppression in the inflamed tissue. Finally, our data underscore the role of immune cell-derived extracellular vesicles in the control of immune responses.

DOI: https://doi.org/10.1038/s41467-021-26134-w
Diabetes Metab J. 2021 Sep;45(5): 655-674

Rho-Kinase as a Therapeutic Target for Nonalcoholic Fatty Liver Diseases.

Inês Sousa-Lima, Hyun Jeong Kim, John Jones, Young-Bum Kim.

  Nonalcoholic fatty liver disease (NAFLD) is a major public health problem and the most common form of chronic liver disease, affecting 25% of the global population. Although NAFLD is closely linked with obesity, insulin resistance, and type 2 diabetes mellitus, knowledge on its pathogenesis remains incomplete. Emerging data have underscored the importance of Rho-kinase (Rho-associated coiled-coil-containing kinase [ROCK]) action in the maintenance of normal hepatic lipid homeostasis. In particular, pharmacological blockade of ROCK in hepatocytes or hepatic stellate cells prevents the progression of liver diseases such as NAFLD and fibrosis. Moreover, mice lacking hepatic ROCK1 are protected against obesity-induced fatty liver diseases by suppressing hepatic de novo lipogenesis. Here we review the roles of ROCK as an indispensable regulator of obesity-induced fatty liver disease and highlight the key cellular pathway governing hepatic lipid accumulation, with focus on de novo lipogenesis and its impact on therapeutic potential. Consequently, a comprehensive understanding of the metabolic milieu linking to liver dysfunction triggered by ROCK activation may help identify new targets for treating fatty liver diseases such as NAFLD.

Keywords:  AMP-activated protein kinase; Diet, high-fat; Lipogenesis; Nonalcoholic fatty liver disease; Rho-kinase

DOI:  https://doi.org/10.4093/dmj.2021.0197
Cell Metab. 2021 Sep 30. pii: S1550-4131(21)00423-X. [Epub ahead of print]

"Sweet death": Fructose as a metabolic toxin that targets the gut-liver axis.

Mark A Febbraio, Michael Karin.

  Glucose and fructose are closely related simple sugars, but fructose has been associated more closely with metabolic disease. Until the 1960s, the major dietary source of fructose was fruit, but subsequently, high-fructose corn syrup (HFCS) became a dominant component of the Western diet. The exponential increase in HFCS consumption correlates with the increased incidence of obesity and type 2 diabetes mellitus, but the mechanistic link between these metabolic diseases and fructose remains tenuous. Although dietary fructose was thought to be metabolized exclusively in the liver, evidence has emerged that it is also metabolized in the small intestine and leads to intestinal epithelial barrier deterioration. Along with the clinical manifestations of hereditary fructose intolerance, these findings suggest that, along with the direct effect of fructose on liver metabolism, the gut-liver axis plays a key role in fructose metabolism and pathology. Here, we summarize recent studies on fructose biology and pathology and discuss new opportunities for prevention and treatment of diseases associated with high-fructose consumption.

Keywords:  NASH; cancer; fructos; gut inflammation; metabolic disease

DOI:  https://doi.org/10.1016/j.cmet.2021.09.004
Gut. 2021 Oct 06. pii: gutjnl-2021-324305. [Epub ahead of print]

Novel therapeutic targets for cholestatic and fatty liver disease.

Michael Trauner, Claudia Daniela Fuchs.

  Cholestatic and non-alcoholic fatty liver disease (NAFLD) share several key pathophysiological mechanisms which can be targeted by novel therapeutic concepts that are currently developed for both areas. Nuclear receptors (NRs) are ligand-activated transcriptional regulators of key metabolic processes including hepatic lipid and glucose metabolism, energy expenditure and bile acid (BA) homoeostasis, as well as inflammation, fibrosis and cellular proliferation. Dysregulation of these processes contributes to the pathogenesis and progression of cholestatic as well as fatty liver disease, placing NRs at the forefront of novel therapeutic approaches. This includes BA and fatty acid activated NRs such as farnesoid-X receptor (FXR) and peroxisome proliferator-activated receptors, respectively, for which high affinity therapeutic ligands targeting specific or multiple isoforms have been developed. Moreover, novel liver-specific ligands for thyroid hormone receptor beta 1 complete the spectrum of currently available NR-targeted drugs. Apart from FXR ligands, BA signalling can be targeted by mimetics of FXR-activated fibroblast growth factor 19, modulation of their enterohepatic circulation through uptake inhibitors in hepatocytes and enterocytes, as well as novel BA derivatives undergoing cholehepatic shunting (instead of enterohepatic circulation). Other therapeutic approaches more directly target inflammation and/or fibrosis as critical events of disease progression. Combination strategies synergistically targeting metabolic disturbances, inflammation and fibrosis may be ultimately necessary for successful treatment of these complex and multifactorial disorders.

Keywords:  fibrosis; inflammation

DOI:  https://doi.org/10.1136/gutjnl-2021-324305
J Lipid Res. 2021 Oct 05. pii: S0022-2275(21)00115-2. [Epub ahead of print] 100133

Hepatic Lysosomal Acid Lipase Overexpression Worsens Hepatic Inflammation in Mice Fed a Western Diet.

Michael W Lopresti, Wenqi Cui, Breann Abernathy, Gavin Fredrickson, Fanta Barrow, Arnav S Desai, Xavier S Revelo, Douglas Mashek.

  Non-alcoholic fatty liver disease (NAFLD) is characterized by the accumulation of lipid droplets (LD) in hepatocytes. NAFLD development and progression is associated with an increase in hepatic cholesterol levels and decreased autophagy and lipophagy flux. Previous studies have shown that the expression of lysosomal acid lipase (LAL, encoded by the gene LIPA), which can hydrolyze both triglyceride and cholesteryl esters, is inversely correlated with the severity of NAFLD. In addition, ablation of LAL activity results in profound NAFLD. Based on this, we predicted that overexpressing LIPA in the livers of mice fed a Western diet would prevent the development of NAFLD. As expected, mice fed the Western diet exhibited numerous markers of NAFLD, including hepatomegaly, lipid accumulation, and inflammation. Unexpectedly, LAL overexpression did not attenuate steatosis and had only minor effects on neutral lipid composition. However, LAL overexpression exacerbated inflammatory gene expression and infiltration of immune cells in mice fed the Western diet. LAL overexpression also resulted in abnormal phagosome accumulation and lysosomal lipid accumulation depending upon the dietary treatment. Overall, we found that hepatic overexpression of LAL drove immune cell infiltration and inflammation and did not attenuate the development of NAFLD, suggesting that targeting LAL expression may not be a viable route to treat NAFLD in humans.

Keywords:  Cholesterol/Cell and tissue; Dietary fat; Inflammation; Lipase/Hepatic; Liver; Lysosomal acid lipase; NAFLD; autophagy; immune infiltration

DOI:  https://doi.org/10.1016/j.jlr.2021.100133
J Biol Chem. 2021 Sep 29. pii: S0021-9258(21)01032-2. [Epub ahead of print] 101229

Sex hormones regulate meta-inflammation in diet-induced obesity in mice.

Mita Varghese, Cameron Griffin, Simin Abrishami, Leila Eter, Nicholas Lanzetta, Layla Hak, Jeremy Clemente, Devyani Agarwal, Arianna Lerner, Maria Westerhoff, Ravi Patel, Emily Bowers, Mohammed Islam, Perla Subbaiah, Kanakadurga Singer.

  Men have a statistically higher risk of metabolic and cardiovascular disease than pre-menopausal women, but the mechanisms mediating these differences are elusive. Chronic inflammation during obesity contributes to disease risk and is significantly more robust in males. Prior work demonstrated that compared to obese males, obese females have reduced pro-inflammatory adipose tissue macrophages (ATMs). Given the paucity of data on how sex hormones contribute to macrophage responses in obesity, we sought to understand the role of sex hormones in promoting obesity-induced myeloid inflammation. We used gonadectomy, estrogen-receptor-deficient (ERα-/-) chimeras, and androgen-insensitive mice to model sex hormone deficiency. These models were evaluated in diet-induced obesity conditions (HFD) and in vitro myeloid assays. We found that ovariectomy increased weight gain and adiposity. Ovariectomized females had increased ATMs and bone marrow (BM) myeloid colonies compared to sham-gonadectomized females. In addition, castrated males exposed to HFD had improved glucose tolerance, insulin sensitivity, and adiposity with fewer Ly6chi monocytes and BM myeloid colonies compared to sham-gonadectomized males, although local adipose inflammation was enhanced. Similar findings were observed in androgen-insensitive mice; however, these mice had fewer CD11c+ ATMs, implying a developmental role for androgens in myelopoiesis and adipose inflammation. We concluded that gonadectomy results in convergence of metabolic and inflammatory responses to HFD between the sexes, and that myeloid ERα contributes minimally to diet-induced inflammatory responses, while loss of androgen-receptor signaling improves metabolic and inflammatory outcomes. These studies demonstrate that sex hormones play a critical role in sex differences in obesity, metabolic dysfunction, and myeloid inflammation.

Keywords:  Obesity; androgens; macrophage; metabolism; myelopoiesis; sex-differences

DOI:  https://doi.org/10.1016/j.jbc.2021.101229
Cell. 2021 Oct 04. pii: S0092-8674(21)01066-7. [Epub ahead of print]

Microbiota triggers STING-type I IFN-dependent monocyte reprogramming of the tumor microenvironment.

Khiem C Lam, Romina E Araya, April Huang, Quanyi Chen, Martina Di Modica, Richard R Rodrigues, Amélie Lopès, Sarah B Johnson, Benjamin Schwarz, Eric Bohrnsen, Alexandria P Cogdill, Catharine M Bosio, Jennifer A Wargo, Maxwell P Lee, Romina S Goldszmid.

  The tumor microenvironment (TME) influences cancer progression and therapy response. Therefore, understanding what regulates the TME immune compartment is vital. Here we show that microbiota signals program mononuclear phagocytes in the TME toward immunostimulatory monocytes and dendritic cells (DCs). Single-cell RNA sequencing revealed that absence of microbiota skews the TME toward pro-tumorigenic macrophages. Mechanistically, we show that microbiota-derived stimulator of interferon genes (STING) agonists induce type I interferon (IFN-I) production by intratumoral monocytes to regulate macrophage polarization and natural killer (NK) cell-DC crosstalk. Microbiota modulation with a high-fiber diet triggered the intratumoral IFN-I-NK cell-DC axis and improved the efficacy of immune checkpoint blockade (ICB). We validated our findings in individuals with melanoma treated with ICB and showed that the predicted intratumoral IFN-I and immune compositional differences between responder and non-responder individuals can be transferred by fecal microbiota transplantation. Our study uncovers a mechanistic link between the microbiota and the innate TME that can be harnessed to improve cancer therapies.

Keywords:  STING; cancer immunology; dendritic cells; immune checkpoint blockade immunotherapy; innate immunity; interferon; macrophages; microbiota; monocytes; tumor microenvironment

DOI:  https://doi.org/10.1016/j.cell.2021.09.019
Cell Metab. 2021 Sep 28. pii: S1550-4131(21)00429-0. [Epub ahead of print]

Molecular aspects of fructose metabolism and metabolic disease.

Mark A Herman, Morris J Birnbaum.

  Excessive sugar consumption is increasingly considered as a contributor to the emerging epidemics of obesity and the associated cardiometabolic disease. Sugar is added to the diet in the form of sucrose or high-fructose corn syrup, both of which comprise nearly equal amounts of glucose and fructose. The unique aspects of fructose metabolism and properties of fructose-derived metabolites allow for fructose to serve as a physiological signal of normal dietary sugar consumption. However, when fructose is consumed in excess, these unique properties may contribute to the pathogenesis of cardiometabolic disease. Here, we review the biochemistry, genetics, and physiology of fructose metabolism and consider mechanisms by which excessive fructose consumption may contribute to metabolic disease. Lastly, we consider new therapeutic options for the treatment of metabolic disease based upon this knowledge.

Keywords:  ALDOB; ChREBP; GLUT5; KHK; NAFLD; TKFC; cardiometabolic disease; fructose; insulin resistance; lipogenesis; steatosis; uric acid

DOI:  https://doi.org/10.1016/j.cmet.2021.09.010
Eur Rev Med Pharmacol Sci. 2021 Sep;pii: 26800. [Epub ahead of print]25(18): 5818-5825

Multifaceted pathogenesis of liver steatosis in inflammatory bowel disease: a systematic review.

R Spagnuolo, L Abenavoli, A Corea, T Larussa, R M Mancina, C Cosco, F Luzza, P Doldo.

OBJECTIVE: Non-Alcoholic Fatty Liver Disease (NAFLD), as a hepatic manifestation of metabolic syndrome (MET)-related obesity, insulin resistance, dyslipidemia, and hypertension, is the main cause of chronic liver disease. Inflammatory Bowel Diseases (IBD), (Crohn's Disease (CD) and Ulcerative Colitis (UC)), are often associated with extraintestinal manifestations. Of these, NAFLD is one of the most frequently reported. To highlight the etiopathogenesis of NAFLD in IBD, we performed a systematic review emphasizing the relationship between NAFLD genetic alterations, metabolic syndrome, and drugs.
MATERIALS AND METHODS: According to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Statement (PRISMA) criteria, we performed a systematic literature search on PubMed, Google Scholar, and Web of Science for literature updated from 2010 to 1 March 2021. Inclusion criteria for studies were observational design and Randomized Controlled Trials (RCTs); written in English; primary research only; based on adult patients, and human research only.
RESULTS: We identified nine studies on the link between NAFLD and IBD. Among these, two described the genetic predisposition to NAFLD of patients with IBD. Four reported an association between MetS and NAFLD in IBD patients. Regarding medications, none of four studies included, detected a relationship between NAFLD onset and IBD treatment (corticosteroids, immunomodulators, methotrexate, or biologics). However, a retrospective study showed a protective effect of anti-TNF alpha therapies against altered liver enzymes.
CONCLUSIONS: In this interplay between genetic, metabolic, drug, and inflammatory factors, the underlying pathogenic mechanisms behind NAFLD in IBD are still far from clear. Further studies are needed to better clarify the role of individual components influencing the development of NAFLD in IBD.

DOI: https://doi.org/10.26355/eurrev_202109_26800