bims-liverm 2022-11-06 papers

bims-liverm

Biomed News

on Liver Metabolism

Issue of 2022–11–06
ten papers selected by

Increased Primary Bile Acids with Ileocolonic Resection Impact Ileal Inflammation and Gut Microbiota in Inflammatory Bowel Disease.
The metabolic conditioning of obesity: A review of the pathogenesis of obesity and the epigenetic pathways that "program" obesity from conception.
Cardiovascular outcomes in patients with biopsy-proven alcohol-related liver disease.
Loss of GPR40 in LDL receptor-deficient mice exacerbates high-fat diet-induced hyperlipidemia and nonalcoholic steatohepatitis.
25-Hydroxyvitamin D Increases Insulin-Stimulated Glucose Uptake by Enhancing Adipocyte Differentiation.
Short-term physical exercise controls age-related hyperinsulinemia and improves hepatic metabolism in aged rodents.
Genetic variation in 9p21, dietary patterns, and insulin sensitivity.
Intrauterine growth retardation affects liver bile acid metabolism in growing pigs: effects associated with the changes of colonic bile acid derivatives.
New insights into mechanisms of endothelial insulin resistance in type 2 diabetes.
The past, present, and future physiology and pharmacology of glucagon.

J Crohns Colitis. 2022 Nov 02. pii: jjac173. [Epub ahead of print]

Increased Primary Bile Acids with Ileocolonic Resection Impact Ileal Inflammation and Gut Microbiota in Inflammatory Bowel Disease.

JRI Live Cell Bank

   BACKGROUND: Most Crohn's disease (CD) patients require surgery. Ileitis recurs after most ileocolectomies and is a critical determinant for outcomes. The impact of ileocolectomy-induced bile acid (BA) perturbations on intestinal microbiota and inflammation are unknown. We characterized relationships between ileocolectomy, stool BA, microbiota, and intestinal inflammation in inflammatory bowel disease (IBD).
METHODS: Validated IBD clinical and endoscopic assessments were prospectively collected. Stool primary and secondary BA concentrations were compared based on ileocolectomy and ileitis status. Primary BA thresholds for ileitis were evaluated. Metagenomic sequencing profiled microbial composition and function. Relationships between ileocolectomy, BA and microbiota were assessed.
RESULTS: In 166 patients, elevated primary and secondary BA existed with ileocolectomy. With ileitis, only primary BA (795 nMol/g vs 398 nMol/g, p=0.009) were higher compared to without ileitis. The optimal primary BA threshold (≥228nMol/g) identified ileitis on multivariable analysis (OR=2.3, p=0.04). Microbial diversity, Faecalibacterium prausnitzii and O-acetylhomoserine aminocarboxypropyltransferase (MetY) were decreased with elevated primary BA. Amongst ileocolectomy patients, only those with elevated primary BA had diversity, F.prausnitzii and MetY reductions. Those with both ileocolectomy and intermediate (p=0.002) or high (≥228nMol/g, p=9.1e-11) ) primary BA had reduced F.prausnitzii compared to without ileocolectomy. Those with ileocolectomy and low (<29.2nMol/g) primary BA had similar F.prausnitzii as those without ileocolectomy (P=0.13). MetY was reduced with ileitis (p=0.02).
CONCLUSIONS: Elevated primary bile acids were associated with ileitis, and reduced microbial diversity, F.prausnitzii abundance, and enzymatic abundance of MetY (acetate and L-methionine producing enzyme expressed by F.prausnitzii) and were the only factor associated with these findings after ileocolectomy.

Keywords:  Acetate; Cholic Acid; Microbiome; Surgery

DOI:  https://doi.org/10.1093/ecco-jcc/jjac173
Front Endocrinol (Lausanne). 2022 ;13 1032491

The metabolic conditioning of obesity: A review of the pathogenesis of obesity and the epigenetic pathways that "program" obesity from conception.

Ananthi Rajamoorthi, Charles A LeDuc, Vidhu V Thaker.

  Understanding the developmental origins of health and disease is integral to overcome the global tide of obesity and its metabolic consequences, including atherosclerotic cardiovascular disease, type 2 diabetes, hyperlipidemia, and nonalcoholic fatty liver disease. The rising prevalence of obesity has been attributed, in part, to environmental factors including the globalization of the western diet and unhealthy lifestyle choices. In this review we argue that how and when such exposures come into play from conception significantly impact overall risk of obesity and later health outcomes. While the laws of thermodynamics dictate that obesity is caused by an imbalance between caloric intake and energy expenditure, the drivers of each of these may be laid down before the manifestation of the phenotype. We present evidence over the last half-century that suggests that the temporospatial evolution of obesity from intrauterine life and beyond is, in part, due to the conditioning of physiological processes at critical developmental periods that results in maladaptive responses to obesogenic exposures later in life. We begin the review by introducing studies that describe an association between perinatal factors and later risk of obesity. After a brief discussion of the pathogenesis of obesity, including the systemic regulation of appetite, adiposity, and basal metabolic rate, we delve into the mechanics of how intrauterine, postnatal and early childhood metabolic environments may contribute to adult obesity risk through the process of metabolic conditioning. Finally, we detail the specific epigenetic pathways identified both in preclinical and clinical studies that synergistically "program" obesity.

Keywords:  cardiometabolic risk; childhood obesity; epigenetics; in utero environment; metabolic programing; postnatal conditions

DOI:  https://doi.org/10.3389/fendo.2022.1032491
Clin Gastroenterol Hepatol. 2022 Nov 01. pii: S1542-3565(22)01011-4. [Epub ahead of print]

Cardiovascular outcomes in patients with biopsy-proven alcohol-related liver disease.

Hannes Hagström, Maja Thiele, Rajani Sharma, Tracey G Simon, Bjorn Roelstraete, Jonas Söderling, Johan Sundström, Jonas F Ludvigsson.

   BACKGROUND & AIMS: Patients with alcohol-related liver disease (ALD) frequently have risk factors for cardiovascular disease (CVD), but their long-term risk of CVD is not well known, especially considering the competing risk of death from liver-related causes. It is further unknown if any excess risk varies across histological subgroups.
METHODS: We investigated the risk of CVD outcomes in 3,488 persons with ALD and an available liver biopsy in Sweden between 1969-2016, compared to a matched reference population (n=15,461). Administrative coding from national diagnostic and histopathology registers were used to define exposures and outcomes. Competing risk regression, taking non-CVD death into account and adjusting for potential confounders, was used to estimate subdistribution hazard ratios (sHRs) for incident CVD up until Dec 31, 2019.
RESULTS: At baseline, patients with ALD had a median age of 58 years, 64% were men, and 2,039 (58%) had cirrhosis on histology. The incidence rate of CVD was 35.6 per 1,000 person-years in ALD compared to 19.0/1,000 in reference individuals. ALD was associated with a two-fold increased short-term risk for CVD compared to matched reference individuals (sHR during the first year after diagnosis=2.29, 95%CI=1.79-2.95), but this risk decreased with time. Incidence rates of CVD were comparable across histological subgroups (ranging from 27.4 CVD cases/1,000 person-years in those with normal histology to 39.2/1,000 in those with cirrhosis).
CONCLUSIONS: Persons with biopsy-proven ALD have increased rates of CVD across histological subgroups compared to matched reference individuals, particularly just after ALD diagnosis. Active surveillance of modifiable CVD risk factors should be considered by clinicians treating patients with ALD.

Keywords:  alcoholic liver disease; epidemiology; ethanol; prognosis

DOI:  https://doi.org/10.1016/j.cgh.2022.10.022
PLoS One. 2022 ;17(11): e0277251

Loss of GPR40 in LDL receptor-deficient mice exacerbates high-fat diet-induced hyperlipidemia and nonalcoholic steatohepatitis.

Zhongyang Lu, Yanchun Li, Ai-Jun Li, Wing-Kin Syn, Stephen A Wank, Maria F Lopes-Virella, Yan Huang.

GPR40, a G protein-coupled receptor for free fatty acids (FFAs), is considered as a therapeutic target for type 2 diabetes mellitus (T2DM) since GPR40 activation in pancreatic beta cells enhances glucose-stimulated insulin secretion. Nonalcoholic fatty liver disease (NAFLD) is a common complication of T2DM or metabolic syndrome (MetS). However, the role of GPR40 in NAFLD associated with T2DM or MetS has not been well established. Given that it is known that cholesterol and FFAs are critically involved in the pathogenesis of nonalcoholic steatohepatitis (NASH) and LDL receptor (LDLR)-deficient mice are a good animal model for human hyperlipidemia including high cholesterol and FFAs, we generated GPR40 and LDLR double knockout (KO) mice in this study to determine the effect of GPR40 KO on hyperlipidemia-promoted NASH. We showed that GPR40 KO increased plasma levels of cholesterol and FFAs in high-fat diet (HFD)-fed LDLR-deficient mice. We also showed that GPR40 KO exacerbated HFD-induced hepatic steatosis, inflammation and fibrosis. Further study demonstrated that GPR40 KO led to upregulation of hepatic CD36 and genes involved in lipogenesis, fatty acid oxidation, fibrosis and inflammation. Finally, our in vitro mechanistic studies showed that while CD36 was involved in upregulation of proinflammatory molecules in macrophages by palmitic acid (PA) and lipopolysaccharide (LPS), GPR40 activation in macrophages exerts anti-inflammatory effects. Taken together, this study demonstrated for the first time that loss of GPR40 in LDLR-deficient mice exacerbated HFD-induced hyperlipidemia, hepatic steatosis, inflammation and fibrosis potentially through a CD36-dependent mechanism, suggesting that GPR40 may play a beneficial role in hyperlipidemia-associated NASH in LDLR-deficient mice.

DOI: https://doi.org/10.1371/journal.pone.0277251
J Nutr Sci Vitaminol (Tokyo). 2022 ;68(5): 420-428

25-Hydroxyvitamin D Increases Insulin-Stimulated Glucose Uptake by Enhancing Adipocyte Differentiation.

Momona Nakashima, Takakazu Mitani.

  Vitamin D and its receptor (vitamin D receptor; VDR) regulate calcium homeostasis in mammals. Recently, studies have shown that serum concentrations of 25-hydroxyvitamin D (25VD) are negatively associated with insulin resistance and the incidence of type 2 diabetes. In adipose tissues, glucose transporter 4 (GLUT4) contributes to insulin-stimulated glucose uptake; however, the effect of 25VD on glucose uptake in adipocytes remains unclear. We examined the role of 25VD in glucose uptake and the differentiation of adipose-derived stromal cells. Insulin-stimulated glucose uptake in adipocytes was increased by treatment with 25VD and decreased by VDR knockdown. The expression levels of GLUT4 were upregulated by 25VD treatment. 25VD exposure increased the expression of adipocyte differentiation-related genes including peroxisome proliferator-activated receptor γ and CCAAT/enhancer-binding proteins through VDR, thereby enhancing the formation of mature adipocytes. Moreover, 25VD increased the expression levels of 11β-hydroxysteroid dehydrogenase 1 (HSD11B1), which catalyzes the conversion of cortisone to cortisol in a concentration-dependent manner. 25VD-stimulated adipocyte differentiation was suppressed by HSD11B1 knockdown. Cortisone together with 25VD enhanced adipocyte differentiation, whereas synthesized glucocorticoid dexamethasone-induced adipocyte differentiation is not promoted by 25VD. Overall, these results indicate that 25VD stimulates adipocyte differentiation through the induction of HSD11B1 expression, leading to increased insulin-induced glucose uptake in adipocytes.

Keywords:  11β-hydroxysteroid dehydrogenase; 25-hydroxyvitamin D; GLUT4; adipocyte; glucocorticoid; glucose uptake; vitamin D

DOI:  https://doi.org/10.3177/jnsv.68.420
J Endocrinol Invest. 2022 Nov 01.

Short-term physical exercise controls age-related hyperinsulinemia and improves hepatic metabolism in aged rodents.

V R Muñoz, R C Gaspar, M C S Mancini, R D de Lima, R F L Vieira, B M Crisol, G C Antunes, J C S Trombeta, I L P Bonfante, F M Simabuco, A S R da Silva, C R Cavaglieri, E R Ropelle, D E Cintra, J R Pauli.

   PURPOSE: Aging is associated with changes in glucose homeostasis related to both decreased insulin secretion and/or impaired insulin action, contributing to the high prevalence of type 2 diabetes (T2D) in the elderly population. Additionally, studies are showing that chronically high levels of circulating insulin can also lead to insulin resistance. In contrast, physical exercise has been a strategy used to improve insulin sensitivity and metabolic health. However, the molecular alterations resulting from the effects of physical exercise in the liver on age-related hyperinsulinemia conditions are not yet fully established. This study aimed to investigate the effects of 7 days of aerobic exercise on hepatic metabolism in aged hyperinsulinemic rats (i.e., Wistar and F344) and in Slc2a4+/- mice (hyperglycemic and hyperinsulinemic mice).
RESULTS: Both aged models showed alterations in insulin and glucose tolerance, which were associated with essential changes in hepatic fat metabolism (lipogenesis, gluconeogenesis, and inflammation). In contrast, 7 days of physical exercise was efficient in improving whole-body glucose and insulin sensitivity, and hepatic metabolism. The Slc2a4+/- mice presented significant metabolic impairments (insulin resistance and hepatic fat accumulation) that were improved by short-term exercise training. In this scenario, high circulating insulin may be an important contributor to age-related insulin resistance and hepatic disarrangements in some specific conditions.
CONCLUSION: In conclusion, our data demonstrated that short-term aerobic exercise was able to control mechanisms related to hepatic fat accumulation and insulin sensitivity in aged rodents. These effects could contribute to late-life metabolic health and prevent the development/progression of age-related T2D.

Keywords:  Aging; Hyperinsulinemia; Liver; Physical exercise

DOI:  https://doi.org/10.1007/s40618-022-01947-8
Front Genet. 2022 ;13 988873

Genetic variation in 9p21, dietary patterns, and insulin sensitivity.

Sara Mahdavi, David J A Jenkins, Ahmed El-Sohemy.

  Background: Single nucleotide polymorphisms in the 9p21 region have been associated with cardiovascular disease and to a lesser extent insulin sensitivity. Previous studies have focused on older populations, and few have examined the impact of gene-diet interactions. The objective of this study was to determine the interaction between dietary patterns and 9p21 genotypes on insulin sensitivity in young adults from different ethnic groups. Methods: Subjects were 1,333 participants aged 20-29 years from the Toronto Nutrigenomics and Health Study (405 men and 928 women; 776 Caucasians and 557 East Asians). Fasting blood was collected to measure glucose, insulin, c-reactive protein and serum lipids, as well as to isolate DNA for genotyping subjects for five SNPs in 9p21 (rs10757274, rs10757278, rs1333049, rs2383206, and rs4977574). Insulin resistance (HOMA-IR) and beta-cell dysfunction (HOMA-Beta) were calculated from fasting insulin and glucose concentrations. The Toronto-modified Harvard 196-item semi-quantitative food frequency questionnaire was used to measure dietary intake over 1 month and principal components analysis was used to identify three dietary patterns (Prudent, Western and Eastern). ANOVA and ANCOVA were used to examine gene-diet interactions on markers of insulin sensitivity. Results: Significant gene-diet interactions on insulin sensitivity using HOMA-IR were observed with all five SNPs, which remained significant after adjusting for covariates (p < 0.05). Among those who were homozygous for the 9p21 risk allele (rs1333049), fasting insulin was 40% higher in those who were consuming a low-prudent diet compared to those consuming a high-prudent diet (p < 0.05). No differences were observed between those following a low versus high-prudent diet among those who did not carry a 9p21 risk allele. Similar findings were observed with HOMA-Beta, however, the association was only significant for rs10757274 (p = 0.04). Conclusion: Our findings suggest that a prudent dietary pattern may protect against the effects of 9p21 risk genotypes on insulin sensitivity.

Keywords:  9p21; gene-diet interactions; insulin sensitivity; nutrigenetics; nutrigenomics; personalized nutrition; precision nutrition

DOI:  https://doi.org/10.3389/fgene.2022.988873
J Anim Sci Biotechnol. 2022 Nov 02. 13(1): 117

Intrauterine growth retardation affects liver bile acid metabolism in growing pigs: effects associated with the changes of colonic bile acid derivatives.

Yang Liu, Md Abul Kalam Azad, Wanghong Zhang, Liang Xiong, Francois Blachier, Zugong Yu, Xiangfeng Kong.

   BACKGROUND: Intrauterine growth retardation (IUGR) is associated with severely impaired nutrient metabolism and intestinal development of pigs. Our previous study found that IUGR altered intestinal microbiota and metabolites in the colon. However, the consequences of IUGR on bile acid metabolism in pigs remained unclear. The present study aimed to investigate the bile acid metabolism in the liver and the profile of bile acid derivatives in the colon of growing pigs with IUGR using bile acid targeted metabolomics. Furthermore, we determined correlations between colonic microbiota composition and metabolites of IUGR and normal birth weight (NBW) pigs at different growth stages that were 7, 21, and 28-day-old, and the average body weight (BW) of 25, 50, and 100 kg of the NBW pigs.
RESULTS: The results showed that the plasma total bile acid concentration was higher (P < 0.05) at the 25 kg BW stage and tended to increase (P = 0.08) at 28-day-old in IUGR pigs. The hepatic gene expressions related to bile acid synthesis (CYP7A1, CYP27A1, and NTCP) were up-regulated (P < 0.05), and the genes related to glucose and lipid metabolism (ATGL, HSL, and PC) were down-regulated (P < 0.05) at the 25 kg BW stage in IUGR pigs when compared with the NBW group. Targeted metabolomics analysis showed that 29 bile acids and related compounds were detected in the colon of pigs. The colonic concentrations of dehydrolithocholic acid and apocholic acid were increased (P < 0.05), while isodeoxycholic acid and 6,7-diketolithocholic acid were decreased (P < 0.05) in IUGR pigs, when compared with the NBW pigs at the 25 kg BW stage. Moreover, Spearman's correlation analysis revealed that colonic Unclassified_[Mogibacteriaceae], Lachnospira, and Slackia abundances were negatively correlated (P < 0.05) with dehydrolithocholic acid, as well as the Unclassified_Clostridiaceae abundance with 6,7-diketolithocholic acid at the 25 kg BW stage.
CONCLUSIONS: These findings suggest that IUGR could affect bile acid and glucolipid metabolism in growing pigs, especially at the 25 kg BW stage, these effects being paralleled by a modification of bile acid derivatives concentrations in the colonic content. The plausible links between these modified parameters are discussed.

Keywords:  Bile acid metabolism; Glucolipid metabolism; Intestinal microbiota; Intrauterine growth retardation; Pigs

DOI:  https://doi.org/10.1186/s40104-022-00772-6
Am J Physiol Heart Circ Physiol. 2022 Nov 04.

New insights into mechanisms of endothelial insulin resistance in type 2 diabetes.

Jaume Padilla, Camila Manrique-Acevedo, Luis A Martinez-Lemus.

  Insulin resistance in the vasculature is a hallmark of type 2 diabetes (T2D) and blunting of insulin-induced vasodilation is its primary consequence. Individuals with T2D exhibit a marked impairment in insulin-induced dilation in resistance arteries across vascular beds. Importantly, reduced insulin-stimulated vasodilation and blood flow to skeletal muscle limits glucose uptake and contributes to impaired glucose control in T2D. The study of mechanisms responsible for the suppressed vasodilatory effects of insulin has been a growing topic of interest not only for its association with glucose control and extension to T2D but also for its relationship with cardiovascular disease development and progression. In this mini-review, we integrate findings from recent studies by our group with the existing literature focused on the mechanisms underlying endothelial insulin resistance in T2D.

Keywords:  diabetes; glucose control; insulin resistance; obesity; vascular dysfunction

DOI:  https://doi.org/10.1152/ajpheart.00537.2022
Cell Metab. 2022 Nov 01. pii: S1550-4131(22)00452-1. [Epub ahead of print]34(11): 1654-1674

The past, present, and future physiology and pharmacology of glucagon.

Megan E Capozzi, David A D'Alessio, Jonathan E Campbell.

  The evolution of glucagon has seen the transition from an impurity in the preparation of insulin to the development of glucagon receptor agonists for use in type 1 diabetes. In type 2 diabetes, glucagon receptor antagonists have been explored to reduce glycemia thought to be induced by hyperglucagonemia. However, the catabolic actions of glucagon are currently being leveraged to target the rise in obesity that paralleled that of diabetes, bringing the pharmacology of glucagon full circle. During this evolution, the physiological importance of glucagon advanced beyond the control of hepatic glucose production, incorporating critical roles for glucagon to regulate both lipid and amino acid metabolism. Thus, it is unsurprising that the study of glucagon has left several paradoxes that make it difficult to distill this hormone down to a simplified action. Here, we describe the history of glucagon from the past to the present and suggest some direction to the future of this field.

Keywords:  diabetes; glucagon; glucose; insulin; α cells

DOI:  https://doi.org/10.1016/j.cmet.2022.10.001