bims-liverm 2022-11-13 papers

bims-liverm

Biomed News

on Liver Metabolism

Issue of 2022–11–13
eleven papers selected by

Impaired Diurnal Pattern of Meal Tolerance and Insulin Sensitivity in Type 2 Diabetes: Implications for Therapy.
Hypomagnesemia and Cardiovascular Risk in Type 2 Diabetes.
Fatty Acid Transport and Signaling: Mechanisms and Physiological Implications.
Linking Nonalcoholic Fatty Liver Disease and Brain Disease: Focusing on Bile Acid Signaling.
Association between hepatic steatosis and fibrosis with measures of insulin sensitivity in patients with severe obesity and type 2 diabetes - a cross-sectional study.
Mechanisms and pharmacotherapy of hypertension associated with type 2 diabetes.
Proinflammatory Polyphosphate Increases in Plasma of Obese Children with Insulin Resistance and Adults with Severe Type 2 Diabetes.
The role of Stearoyl-CoA desaturase in hepatic de novo lipogenesis.
New insights into the interplay between intestinal flora and bile acids in inflammatory bowel disease.
Plasma Metabolomic and Lipidomic Profiling of Metabolic Dysfunction-Associated Fatty Liver Disease in Humans Using an Untargeted Multiplatform Approach.
Regulation of Hepatocyte Nuclear Factor 4α Attenuated Lipotoxicity but Increased Bile Acid Toxicity in Non-Alcoholic Fatty Liver Disease.

Diabetes. 2022 Nov 08. pii: db220238. [Epub ahead of print]

Impaired Diurnal Pattern of Meal Tolerance and Insulin Sensitivity in Type 2 Diabetes: Implications for Therapy.

Yogesh Yadav, Davide Romeres, Claudio Cobelli, Chiara Dalla Man, Rickey Carter, Ananda Basu, Rita Basu.

To assess the diurnal patterns of postprandial glucose tolerance and insulin sensitivity, 19 type 2 diabetes [8F; 60±11 yrs.; BMI: 32±5 kg/m2] and 19 anthropometrically matched non-diabetic (ND) subjects [11 F; 53±12 yrs.; BMI: 29±5 kg/m2] were studied during breakfast (B), lunch (L), and dinner (D) with identical mixed meals (75 gm carbs) on three consecutive days in a randomized Latin square design. Three stable isotopes of glucose were utilized to estimate meal fluxes and mathematical models used for estimating indices of insulin action and beta cell function. Post meal glucose excursions were higher at D vs B and D vs L in type 2 diabetes (p<0.05) while in ND they were higher at D vs. B (p=0.025) and L vs B (P=0.04). Insulin iAUC was highest at B as compared to L and D in type 2 diabetes while there were no differences observed in ND. Disposition Index (DI) was higher at B than at L (p<0.01) and D (p<0.001) in ND subjects while DI was low with unchanging pattern across B-L-D in type 2 diabetes. Furthermore, between meal differences in beta cell responsivity to glucose (φ) and insulin sensitivity (SI) were concurrent with changes in DI within groups. Fasting and post meal glucose, insulin, C-peptide concentrations, along with estimates of endogenous glucose production (EGP), rate of glucose disappearance (Rd), SI, Φ, hepatic extraction of insulin (HE), insulin secretion rate, extracted insulin and DI were altered in type 2 diabetes compared to ND (P < 0.011 for all).The data shows diurnal pattern of postprandial glucose tolerance in overweight otherwise glucose tolerant ND individuals differs from overweight type 2 diabetes. The results not only provide valuable insight into management strategies for better glycemic control in people with type 2 diabetes but also improved understanding of daytime glucose metabolism in overweight individuals without impaired glucose tolerance or overt diabetes.

DOI: https://doi.org/10.2337/db22-0238
Endocr Rev. 2022 Nov 08. pii: bnac028. [Epub ahead of print]

Hypomagnesemia and Cardiovascular Risk in Type 2 Diabetes.

Lynette J Oost, Cees J Tack, Jeroen H F de Baaij.

  Hypomagnesemia is tenfold more common in individuals with type 2 diabetes (T2D), compared to the healthy population. Factors that are involved in this high prevalence are low Mg2+ intake, gut microbiome composition, medication use and presumably genetics. Hypomagnesemia is associated with insulin resistance, which subsequently increases the risk to develop T2D or deteriorates glycaemic control in existing diabetes. Mg2+ supplementation decreases T2D associated features like dyslipidaemia and inflammation; which are important risk factors for cardiovascular disease (CVD). Epidemiological studies have shown an inverse association between serum Mg2+ and the risk to develop heart failure (HF), atrial fibrillation (AF) and microvascular disease in T2D. The potential protective effect of Mg2+ on HF and AF may be explained by reduced oxidative stress, fibrosis and electrical remodeling in the heart. In microvascular disease, Mg2+ reduces the detrimental effects of hyperglycemia and improves endothelial dysfunction. Though, clinical studies assessing the effect of long-term Mg2+ supplementation on CVD incidents are lacking and gaps remain on how Mg2+ may reduce CVD risk in T2D. Despite the high prevalence of hypomagnesemia in people with T2D, routine screening of Mg2+ deficiency to provide Mg2+ supplementation when needed is not implemented in clinical care as sufficient clinical evidence is lacking. In conclusion, hypomagnesemia is common in people with T2D and is both involved as cause, probably through molecular mechanisms leading to insulin resistance, and consequence and is prospectively associated with development of HF, AF and microvascular complications. Whether long-term supplementation of Mg2+ is beneficial, however, remains to be determined.

Keywords:  atrial fibrillation; cardiovascular disease; heart failure; macrovascular disease; microvascular disease; type 2 diabetes

DOI:  https://doi.org/10.1210/endrev/bnac028
Annu Rev Physiol. 2022 Nov 08.

Fatty Acid Transport and Signaling: Mechanisms and Physiological Implications.

Dmitri Samovski, Miriam Jacome-Sosa, Nada A Abumrad.

Long-chain fatty acids (FAs) are components of plasma membranes and an efficient fuel source and also serve as metabolic regulators through FA signaling mediated by membrane FA receptors. Impaired tissue FA uptake has been linked to major complications of obesity, including insulin resistance, cardiovascular disease, and type 2 diabetes. Fatty acid interactions with a membrane receptor and the initiation of signaling can modify pathways related to nutrient uptake and processing, cell proliferation or differentiation, and secretion of bioactive factors. Here, we review the major membrane receptors involved in FA uptake and FA signaling. We focus on two types of membrane receptors for long-chain FAs: CD36 and the G protein-coupled FA receptors FFAR1 and FFAR4. We describe key signaling pathways and metabolic outcomes for CD36, FFAR1, and FFAR4 and highlight the parallels that provide insight into FA regulation of cell function. Expected final online publication date for the Annual Review of Physiology, Volume 85 is February 2023. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

DOI: https://doi.org/10.1146/annurev-physiol-032122-030352
Int J Mol Sci. 2022 Oct 27. pii: 13045. [Epub ahead of print]23(21):

Linking Nonalcoholic Fatty Liver Disease and Brain Disease: Focusing on Bile Acid Signaling.

Zi-Lin Ren, Chang-Xiang Li, Chong-Yang Ma, Dan Chen, Jia-Hui Chen, Wen-Xiu Xu, Cong-Ai Chen, Fa-Feng Cheng, Xue-Qian Wang.

  A metabolic illness known as non-alcoholic fatty liver disease (NAFLD), affects more than one-quarter of the world's population. Bile acids (BAs), as detergents involved in lipid digestion, show an abnormal metabolism in patients with NAFLD. However, BAs can affect other organs as well, such as the brain, where it has a neuroprotective effect. According to a series of studies, brain disorders may be extrahepatic manifestations of NAFLD, such as depression, changes to the cerebrovascular system, and worsening cognitive ability. Consequently, we propose that NAFLD affects the development of brain disease, through the bile acid signaling pathway. Through direct or indirect channels, BAs can send messages to the brain. Some BAs may operate directly on the central Farnesoid X receptor (FXR) and the G protein bile acid-activated receptor 1 (GPBAR1) by overcoming the blood-brain barrier (BBB). Furthermore, glucagon-like peptide-1 (GLP-1) and the fibroblast growth factor (FGF) 19 are released from the intestine FXR and GPBAR1 receptors, upon activation, both of which send signals to the brain. Inflammatory, systemic metabolic disorders in the liver and brain are regulated by the bile acid-activated receptors FXR and GPBAR1, which are potential therapeutic targets. From a bile acid viewpoint, we examine the bile acid signaling changes in NAFLD and brain disease. We also recommend the development of dual GPBAR1/FXR ligands to reduce side effects and manage NAFLD and brain disease efficiently.

Keywords:  FXR; GPBAR1; NAFLD; bile acids; brain disease

DOI:  https://doi.org/10.3390/ijms232113045
BMC Gastroenterol. 2022 Nov 07. 22(1): 448

Association between hepatic steatosis and fibrosis with measures of insulin sensitivity in patients with severe obesity and type 2 diabetes - a cross-sectional study.

Kathrine Aglen Seeberg, Dag Hofsø, Heidi Borgeraas, John Olav Grimnes, Farhat Fatima, Lars Thomas Seeberg, Nils Petter Kvan, Marius Svanevik, Jens Kristoffer Hertel, Jøran Hjelmesæth.

   BACKGROUND: Obesity, non-alcoholic fatty liver disease (NAFLD) and insulin resistance are three pathological conditions highly correlated, but this relationship is not fully elucidated. Hence, we aimed to assess the association of hepatic steatosis and fibrosis with different measures of insulin sensitivity in patients with severe obesity and type 2 diabetes mellitus (T2DM).
METHODS: A cross-sectional study (Oseberg trial) including patients with T2DM referred for bariatric surgery at Vestfold Hospital Trust, Norway. Magnetic resonance imaging (MRI) and the enhanced liver fibrosis (ELF) test was used for estimation of liver fat fraction (LFF) and degree of fibrosis, respectively. Oral and intravenous glucose tolerance tests were applied for estimation of insulin sensitivity (HOMA2S, Matsuda ISI and MinMod SI).
RESULTS: A total of 100 patients (mean [SD] age 47.5 [9.7] years, 65% women, BMI 42.0 [5.3] kg/m2 and 98% with metabolic syndrome) were included in the analyses. The mean (SD) LFF in the total population was 19.1 (11.5), and the mean (SD) ELF score was 8.46 (0.84), a value representing moderate fibrosis. LFF was inversely associated with HOMA2S and Matsuda ISI, and both measures were significantly higher in the no or low-grade steatosis group compared with the medium-to-high grade steatosis group (mean difference [95% CI] 5.9 [2.2-9.6]%, Cohen's d = 0.75), and (0.7 [0.3-1.1], Cohen's d = 0.80, respectively). There was no association between LFF, as a categorical or continuous variable, and MinMod SI. The proportions of patients with none to mild fibrosis, moderate fibrosis and severe fibrosis were 14, 78 and 6%, respectively, and there were no significant associations between level of fibrosis and measures of insulin sensitivity.
CONCLUSIONS: Patients with morbid obesity and T2DM demonstrated high levels of liver fat fraction, and we showed that hepatic steatosis, but not the degree of liver fibrosis, was associated with different measures of insulin sensitivity in patients with severe obesity and T2DM. Further, our results might indicate that the LFF is primarily associated with hepatic, and not peripheral insulin sensitivity. To improve the diagnosis of NAFLD and the prediction of its progression, more studies are needed to reveal the pathological mechanistic pathways involved in NAFLD and insulin sensitivity.
TRIAL REGISTRATION: ClinicalTrials.gov: NCT01778738.

Keywords:  ELF test; Hepatic steatosis; Insulin sensitivity; Liver fat fraction; Liver fibrosis; Severe obesity; Type 2 diabetes mellitus

DOI:  https://doi.org/10.1186/s12876-022-02550-0
Biochem Pharmacol. 2022 Nov 02. pii: S0006-2952(22)00398-7. [Epub ahead of print]206 115304

Mechanisms and pharmacotherapy of hypertension associated with type 2 diabetes.

Vijayvardhan Kamalumpundi, Elham Shams, Cally Tucker, Linhai Cheng, Joshua Peterson, Sanmati Thangavel, Oloigbe Ofori, Marcelo Correia.

  Type 2 diabetes is often complicated with hypertension, such that 73.6 % of patients ≥ 18 years with type 2 diabetes also have hypertension. With increasing age, the risk of developing these conditions rises significantly. Co-existence of type 2 diabetes and hypertension suggests that there are overlapping genetic, physiologic, and environmental factors at play. Research has shown several overlying metabolic abnormalities including sympathetic nervous system overactivation, insulin resistance, inflammatory and endothelial dysfunction, deleterious expression of microRNAs, and obstructive sleep apnea. Though diet and physical activity are the mainstays of treatment early in the disease course, they are generally not a viable long-term strategy. Treatment with novel hypoglycemic and anti-hypertensive medications can greatly assist in preventing long-term complications of these chronic conditions. Recognition of the common causes and consequences of type 2 diabetes and comorbid hypertension allows for a robust response towards being proactive regarding prevention and treatment of this unique patient population. Thus, the purpose of this current review is four-part: to (1) review the latest discoveries into the mechanisms of hypertension in the setting of type 2 diabetes, (2) discuss the latest treatments of hypertension with a brief discussion about novel hypoglycemic agents in patients with type 2 diabetes, (3) summarize blood pressure targets and (4) to address evidence gaps in treating patients with diabetes and resistant hypertension, and elderly individuals with both hypertension and diabetes.

Keywords:  Cardiovascular Disease; Clinical Trials; Diabetes; Hypertension; Metabolic Syndrome; Pharmacotherapy

DOI:  https://doi.org/10.1016/j.bcp.2022.115304
Nutrients. 2022 Nov 01. pii: 4601. [Epub ahead of print]14(21):

Proinflammatory Polyphosphate Increases in Plasma of Obese Children with Insulin Resistance and Adults with Severe Type 2 Diabetes.

Marcela Montilla, Andrea Liberato, Pablo Ruiz-Ocaña, Ana Sáez-Benito, Manuel Aguilar-Diosdado, Alfonso Maria Lechuga-Sancho, Felix A Ruiz.

  Obesity increases the risk of insulin resistance and type 2 diabetes through increased inflammation at cellular and tissue levels. Therefore, study of the molecular elements involved in obesity-related inflammation may contribute to preventing and controlling it. Inorganic polyphosphate is a natural phosphate polymer that has recently been attracting more attention for its role in inflammation and hemostasis processes. Polyphosphates are one of the main constituents of human platelets, which are secreted after platelet activation. Among other roles, they interact with multiple proteins of the coagulation cascade, trigger bradykinin release, and inhibit the complement system. Despite its importance, determinations of polyphosphate levels in blood plasma had been elusive until recently, when we developed a method to detect these levels precisely. Here, we perform cross sectional studies to evaluate plasma polyphosphate in: 25 children, most of them with obesity and overweight, and 20 adults, half of them with severe type 2 diabetes. Our results show that polyphosphate increases, in a significant manner, in children with insulin resistance and in type 2 diabetes patients. As we demonstrated before that polyphosphate decreases in healthy overweight individuals, these results suggest that this polymer could be an inflammation biomarker in the metabolic disease onset before diabetes.

Keywords:  biomarker; children; inflammation; insulin resistance; obesity; polyphosphate; type 2 diabetes

DOI:  https://doi.org/10.3390/nu14214601
Biochem Biophys Res Commun. 2022 Dec 10. pii: S0006-291X(22)01237-2. [Epub ahead of print]633 81-83

The role of Stearoyl-CoA desaturase in hepatic de novo lipogenesis.

James M Ntambi.

Obesity and the metabolic syndrome are global public health problems. Obesity is currently a worldwide epidemic and public health burden that increases the risk for developing insulin resistance and several chronic diseases such as diabetes, cardiovascular disease and non-alcoholic fatty liver disease. The multifactorial causes of obesity include several genetic, dietary and lifestyle variables that together result in an imbalance between energy intake and energy expenditure. Dietary approaches to limit fat intake are commonly prescribed to achieve the hypocaloric conditions necessary for weight loss. But dietary fat restriction is often accompanied by increased carbohydrate intake, which can dramatically increase endogenous fatty acid synthesis depending upon carbohydrate composition. Since both dietary and endogenously synthesized fatty acids contribute to the whole-body fatty acid pool, obesity can therefore result from excessive fat or carbohydrate consumption.

DOI: https://doi.org/10.1016/j.bbrc.2022.08.092
World J Clin Cases. 2022 Oct 26. 10(30): 10823-10839

New insights into the interplay between intestinal flora and bile acids in inflammatory bowel disease.

Lie Zheng.

  Intestinal flora plays a key role in nutrient absorption, metabolism and immune defense, and is considered to be the cornerstone of maintaining the health of human hosts. Bile acids synthesized in the liver can not only promote the absorption of fat-soluble substances in the intestine, but also directly or indirectly affect the structure and function of intestinal flora. Under the action of intestinal flora, bile acids can be converted into secondary bile acids, which can be reabsorbed back to the liver through the enterohepatic circulation. The complex dialogue mechanism between intestinal flora and bile acids is involved in the development of intestinal inflammation such as inflammatory bowel disease (IBD). In this review, the effects of intestinal flora, bile acids and their interactions on IBD and the progress of treatment were reviewed.

Keywords:  Bile acids; Fecal microbiota transplantation; Inflammatory bowel disease; Intestinal flora; Prebiotics

DOI:  https://doi.org/10.12998/wjcc.v10.i30.10823
Metabolites. 2022 Nov 08. pii: 1081. [Epub ahead of print]12(11):

Plasma Metabolomic and Lipidomic Profiling of Metabolic Dysfunction-Associated Fatty Liver Disease in Humans Using an Untargeted Multiplatform Approach.

Xiangping Lin, Xinyu Liu, Mohamed N Triba, Nadia Bouchemal, Zhicheng Liu, Douglas I Walker, Tony Palama, Laurence Le Moyec, Marianne Ziol, Nada Helmy, Corinne Vons, Guowang Xu, Carina Prip-Buus, Philippe Savarin.

  Metabolic dysfunction-associated fatty liver disease (MAFLD) is a complex disorder that is implicated in dysregulations in multiple biological pathways, orchestrated by interactions between genetic predisposition, metabolic syndromes and environmental factors. The limited knowledge of its pathogenesis is one of the bottlenecks in the development of prognostic and therapeutic options for MAFLD. Moreover, the extent to which metabolic pathways are altered due to ongoing hepatic steatosis, inflammation and fibrosis and subsequent liver damage remains unclear. To uncover potential MAFLD pathogenesis in humans, we employed an untargeted nuclear magnetic resonance (NMR) spectroscopy- and high-resolution mass spectrometry (HRMS)-based multiplatform approach combined with a computational multiblock omics framework to characterize the plasma metabolomes and lipidomes of obese patients without (n = 19) or with liver biopsy confirmed MAFLD (n = 63). Metabolite features associated with MAFLD were identified using a metabolome-wide association study pipeline that tested for the relationships between feature responses and MAFLD. A metabolic pathway enrichment analysis revealed 16 pathways associated with MAFLD and highlighted pathway changes, including amino acid metabolism, bile acid metabolism, carnitine shuttle, fatty acid metabolism, glycerophospholipid metabolism, arachidonic acid metabolism and steroid metabolism. These results suggested that there were alterations in energy metabolism, specifically amino acid and lipid metabolism, and pointed to the pathways being implicated in alerted liver function, mitochondrial dysfunctions and immune system disorders, which have previously been linked to MAFLD in human and animal studies. Together, this study revealed specific metabolic alterations associated with MAFLD and supported the idea that MAFLD is fundamentally a metabolism-related disorder, thereby providing new perspectives for diagnostic and therapeutic strategies.

Keywords:  NMR; lipidomics; mass spectrometry; metabolic dysfunction-associated fatty liver disease; metabolomics; multiblock analysis

DOI:  https://doi.org/10.3390/metabo12111081
Life (Basel). 2022 Oct 22. pii: 1682. [Epub ahead of print]12(11):

Regulation of Hepatocyte Nuclear Factor 4α Attenuated Lipotoxicity but Increased Bile Acid Toxicity in Non-Alcoholic Fatty Liver Disease.

Yoon Jin Roh, Yun Kim, Jae Sun Lee, Ju Hee Oh, Seung Min Lee, Eileen Laurel Yoon, Sung Ryol Lee, Dae Won Jun.

  Hepatocyte nuclear factor 4 alpha (HNF4α) is a key master transcriptional factor for hepatic fat and bile acid metabolic pathways. We aimed to investigate the role of HNF4α in non-alcoholic fatty liver disease (NAFLD). The role of HNF4α was evaluated in free fatty acid-induced lipotoxicity and chenodeoxycholic acid (CDCA)-induced bile acid toxicity. Furthermore, the role of HNF4α was evaluated in a methionine choline deficiency (MCD)-diet-induced NAFLD model. The overexpression of HNF4α reduced intracellular lipid contents and attenuated palmitic acid (PA)-induced lipotoxicity. However, the protective effects of HNF4α were reversed when CDCA was used in a co-treatment with PA. HNF4α knockdown recovered cell death from bile acid toxicity. The inhibition of HNF4α decreased intrahepatic inflammation and the NAFLD activity score in the MCD model. Hepatic HNF4α inhibition can attenuate bile acid toxicity and be more effective as a therapeutic strategy in NAFLD patients; however, it is necessary to study the optimal timing of HNF4α inhibition.

Keywords:  bile acid toxicity; hepatocyte nuclear factor 4 alpha; lipotoxicity; non-alcoholic fatty liver disease; steatohepatitis

DOI:  https://doi.org/10.3390/life12111682