Relationship between adipose tissue dysfunction, Vitamin D deficiency and the pathogenesis of non-alcoholic fatty liver disease

Non-alcoholic fatty liver disease ( NAFLD) is the most common chronic liver disease worldwide. Its pathogenesis is complex and not yet fully understood. Over the years many studies have proposed various pathophysiological hypotheses, among which the currently most widely accepted is the "multiple parallel hits" theory. According to this model, lipid accumulation in the hepatocytes and insulin resistance increase the vulnerability of the liver to many factors that act in a coordinated and cooperative manner to promote hepatic injury, inflammation and fibrosis. Among these factors, adipose tissue dysfunction and subsequent chronic low grade inflammation play a crucial role. Recent studies have shown that vitamin D exerts an immune-regulating action on adipose tissue, and the growing wealth of epidemiological data is demonstrating that hypovitaminosis D is associated with both obesity and NAFLD. Furthermore, given the strong association between these conditions, current findings suggest that vitamin D may be involved in the relationship between adipose tissue dysfunction and NAFLD. The purpose of this review is to provide an overview of recent advances in the pathogenesis of NAFLD in relation to adipose tissue dysfunction, and in the pathophysiology linking vitamin D deficiency with NAFLD and adiposity, together with an overview of the evidence available on the clinical utility of vitamin D supplementation in cases of NAFLD

Increased plasma proneurotensin levels identify NAFLD in adults with and without type 2 diabetes

Context Neurotensin (NT), an intestinal peptide released by fat ingestion, promotes lipid absorption; higher circulating NT levels are associated with type 2 diabetes (T2D), obesity, and cardiovascular disease. Whether NT is related to nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) has not been fully investigated. Objective To study the relationship between plasma proneurotensin 1 to 117 (pro-NT), a stable fragment of the NT precursor hormone, and the presence/severity of NAFLD/NASH and to unravel correlates of increased pro-NT levels. Design/Setting/Participants For this cross-sectional study, 60 obese individuals undergoing bariatric surgery for clinical purposes were recruited. The association between pro-NT and NAFLD was further investigated in 260 consecutive subjects referred to our outpatient clinics for metabolic evaluations, including liver ultrasonography. The study population underwent complete metabolic characterization; in the obese cohort, liver biopsies were performed during surgery. Main Outcome Measures Plasma pro-NT levels in relation to NAFLD/NASH. Results Obese subjects with biopsy-proven NAFLD (53%) had significantly higher plasma pro-NT than those without NAFLD (183.6 ± 81.4 vs 86.7 ± 56.8 pmol/L, P < 0.001). Greater pro-NT correlated with NAFLD presence (P < 0.001) and severity (P < 0.001), age, female sex, insulin resistance, and T2D. Higher pro-NT predicted NAFLD with an area under receiver operating characteristic curve of 0.836 [95% confidence interval (CI), 0.73 to 0.94; P < 0.001]. Belonging to the highest pro-NT quartile correlated with increased NAFLD risk (odds ratio, 2.62; 95% CI, 1.08 to 6.40) after adjustment for confounders. The association between higher pro-NT and NAFLD was confirmed in the second cohort independently from confounders. Conclusions Increased plasma pro-NT levels identify the presence/severity of NAFLD; in dysmetabolic individuals, NT may specifically promote hepatic fat accumulation through mechanisms likely related to increased insulin resistance. © 2018 Endocrine Society

Phenotypical heterogeneity linked to adipose tissue dysfunction in patients with type 2 diabetes

Adipose tissue (AT) inflammation leads to increased free fatty acid (FFA) efflux and ectopic fat deposition, but whether AT dysfunction drives selective fat accumulation in specific sites remains unknown. The aim of the present study was to investigate the correlation between AT dysfunction, hepatic/pancreatic fat fraction (HFF, PFF) and the associated metabolic phenotype in patients with Type 2 diabetes (T2D). Sixty-five consecutive T2D patients were recruited at the Diabetes Centre of Sapienza University, Rome, Italy. The study population underwent clinical examination and blood sampling for routine biochemistry and calculation of insulin secretion [homoeostasis model assessment of insulin secretion (HOMA-β%)] and insulin-resistance [homoeostasis model assessment of insulin resistance (HOMA-IR) and adipose tissue insulin resistance (ADIPO-IR)] indexes. Subcutaneous (SAT) and visceral (VAT) AT area, HFF and PFF were determined by magnetic resonance. Some 55.4% of T2D patients had non-alcoholic fatty liver disease (NAFLD); they were significantly younger and more insulin-resistant than non-NAFLD subjects. ADIPO-IR was the main determinant of HFF independently of age, sex, HOMA-IR, VAT, SAT and predicted severe NAFLD with the area under the receiver operating characteristic curve (AUROC)=0.796 (95% confidence interval: 0.65-0.94, P=0.001). PFF was independently associated with increased total adiposity but did not correlate with AT dysfunction, insulin resistance and secretion or NAFLD. The ADIPO-IR index was capable of predicting NAFLD independently of all confounders, whereas it did not seem to be related to intrapancreatic fat deposition; unlike HFF, higher PFF was not associated with relevant alterations in the metabolic profile. In conclusion, the presence and severity of AT dysfunction may drive ectopic fat accumulation towards specific targets, such as VAT and liver, therefore evaluation of AT dysfunction may contribute to the identification of different risk profiles among T2D patients

No effects of oral vitamin D supplementation on non-alcoholic fatty liver disease in patients with type 2 diabetes: a randomized, double-blind, placebo-controlled trial

Background: Non-alcoholic fatty liver disease (NAFLD) is the most common hepatic disorder worldwide, reaching prevalence up to 90 % in obese patients with type 2 diabetes (T2D), and representing an independent risk factor for cardiovascular mortality. Furthermore, the coexistence of T2D and NAFLD leads to higher incidence of diabetes’ complications and additive detrimental liver outcomes. The existence of a close association between NAFLD and hypovitaminosis D, along with the anti-inflammatory and insulin-sensitizing properties of vitamin D, have been largely described, but vitamin D effects on hepatic fat content have never been tested in a randomized controlled trial. We assessed the efficacy and safety of 24-week oral high-dose vitamin D supplementation in T2D patients with NAFLD. Methods: This randomized, double-blind, placebo-controlled trial was carried out at the Diabetes Centre of Sapienza University, Rome, Italy, to assess oral treatment with cholecalciferol (2000 IU/day) or placebo in T2D patients with NAFLD. The primary endpoint was reduction of hepatic fat fraction (HFF) measured by magnetic resonance; as hepatic outcomes, we also investigated changes in serum transaminases, CK18-M30, N-terminal Procollagen III Propeptide (P3NP) levels, and Fatty Liver Index (FLI). Secondary endpoints were improvement in metabolic (fasting glycaemia, HbA1c, lipids, HOMA-IR, HOMA-β, ADIPO-IR, body fat distribution) and cardiovascular (ankle-brachial index, intima-media thickness, flow-mediated dilatation) parameters from baseline to end of treatment. Results: Sixty-five patients were randomized, 26 (cholecalciferol) and 29 (placebo) subjects completed the study. 25(OH) vitamin D significantly increased in the active treated group (48.15 ± 23.7 to 89.80 ± 23.6 nmol/L, P < 0.001); however, no group differences were found in HFF, transaminases, CK18-M30, P3NP levels or FLI after 24 weeks. Vitamin D neither changed the metabolic profile nor the cardiovascular parameters. Conclusions: Oral high-dose vitamin D supplementation over 24 weeks did not improve hepatic steatosis or metabolic/cardiovascular parameters in T2D patients with NAFLD. Studies with a longer intervention period are warranted for exploring the effect of long time exposure to vitamin D

Increased PARylation impacts the DNA methylation process in type 2 diabetes mellitus

Epigenetic modifications, such as DNA methylation, can influence the genetic susceptibility to type 2 diabetes mellitus (T2DM) and the progression of the disease. Our previous studies demonstrated that the regulation of the DNA methylation pattern involves the poly(ADP-ribosyl)ation (PARylation) process, a post-translational modification of proteins catalysed by the poly(ADP-ribose) polymerase (PARP) enzymes. Experimental data showed that the hyperactivation of PARylation is associated with impaired glucose metabolism and the development of T2DM. Aims of this case-control study were to investigate the association between PARylation and global and site-specific DNA methylation in T2DM and to evaluate metabolic correlates

Vitamin D and Metabolic Dysfunction-Associated Fatty Liver Disease (MAFLD): An Update

Non-alcoholic fatty liver disease (NAFLD) is the first cause of chronic liver disease worldwide; it ranges from simple steatosis to steatohepatitis (NASH) and, potentially, cirrhosis and hepatocarcinoma. NAFLD is also an independent risk factor for type 2 diabetes, cardiovascular diseases, and mortality. As it is largely associated with insulin resistance and related disorders, NAFLD has been recently re-named as Metabolic dysfunction-Associated Fatty Liver Disease (MAFLD). At present, there are no approved pharmacological treatments for this condition. Vitamin D is a molecule with extensive anti-fibrotic, anti-inflammatory, and insulin-sensitizing properties, which have been proven also in hepatic cells and is involved in immune-metabolic pathways within the gut–adipose tissue–liver axis. Epidemiological data support a relationship hypovitaminosis D and the presence of NAFLD and steatohepatitis (NASH); however, results from vitamin D supplementation trials on liver outcomes are controversial. This narrative review provides an overview of the latest evidence on pathophysiological pathways connecting vitamin D to NAFLD, with emphasis on the effects of vitamin D treatment in MAFLD by a nonsystematic literature review of PubMed published clinical trials. This article conforms to the Scale for Assessment of Narrative Review Articles (SANRA) guidelines. Evidence so far available supports the hypothesis of potential benefits of vitamin D supplementation in selected populations of NAFLD patients, as those with shorter disease duration and mild to moderate liver damage

Vitamin d supplementation and non-alcoholic fatty liver disease: Present and future

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic hepatic disease throughout the Western world and is recognized as the main cause of cryptogenic cirrhosis; however, the identification of an effective therapy for NAFLD is still a major challenge. Vitamin D deficiency is a wide-spread condition which reaches epidemic proportions in industrialized countries, mainly in relation to current lifestyle and limited dietary sources. Epidemiological studies point towards an association between hypovitaminosis D and the presence of NAFLD and steatohepatitis (NASH), independently of confounders such as obesity and insulin resistance. Furthermore, several pieces of experimental data have shown the anti-fibrotic, anti-inflammatory and insulin-sensitizing properties exerted by vitamin D on hepatic cells. However, results from trials evaluating the effects of oral vitamin D supplementation on liver damage in NAFLD and NASH are controversial. The aim of this review is to give an overview of the evidence currently available from clinical trials and to discuss possible shortcomings and new strategies to be considered in future investigations

Dipeptidyl peptidase-4 inhibitors and bone metabolism: is vitamin D the link?

Abstract AIMS: Dipeptidyl peptidase-4 inhibitors (DPP4-Is) represent a promising class of agents for type 2 diabetes treatment. Experimental models and clinical studies have reported positive effects of DPP4-Is on bone; however, how DPP4-Is positively impact bone homeostasis in humans remains an unanswered question. Aim of this study investigated the relationship between treatment with DPP4-Is and vitamin D balance in patients with type 2 diabetes. METHODS: This is a cross-sectional study. A total of 295 consecutive individuals with type 2 diabetes referring to our diabetes outpatient clinics were enrolled; among them, 53 % were in treatment with DPP4-Is. Metabolic profile and routine biochemistry were assessed by standard methods; serum 25(OH) vitamin D levels [25(OH)D] were measured by colorimetric method (LAISON, DiaSorin). RESULTS: DPP4-Is-treated participants had significantly higher serum 25(OH)D levels then those undertaking other antidiabetic therapies (18.4 ± 10.7 vs. 14.9 ± 8.6 ng/ml, p = 0.004); this association persisted after adjusting for all major confounders. Increased 25(OH)D concentrations also correlated with the duration of DPP4-Is treatment and with a stronger DPP4 inhibitory activity. CONCLUSIONS: DPP4-Is treatment is associated with improved vitamin D balance in people with type 2 diabetes; our findings suggest that vitamin D may underlie the link between DPP4-Is and bone metabolism

Dipeptidyl Peptidase 4 (DPP4) as A Novel Adipokine: Role in Metabolism and Fat Homeostasis

Dipeptidyl peptidase 4 (DPP4) is a molecule implicated in the regulation of metabolic homeostasis and inflammatory processes, and it exerts its main action through its enzymatic activity. DPP4 represents the enzyme most involved in the catabolism of incretin hormones; thus, its activity impacts appetite, energy balance, and the fine regulation of glucose homeostasis. Indeed, DPP4 inhibitors represent a class of antidiabetic agents widely used for the treatment of Type 2 diabetes mellitus (T2DM). DPP4 also acts as an adipokine and is mainly secreted by the adipose tissue, mostly from mature adipocytes of the visceral compartment, where it exerts autocrine and paracrine activities. DPP4 can disrupt insulin signaling within the adipocyte and in other target cells and tissues, where it also favors the development of a proinflammatory environment. This is likely at the basis of the presence of elevated circulating DPP4 levels in several metabolic diseases. In this review, we summarize the most recent evidence of the role of the DPP4 as an adipokine-regulating glucose/insulin metabolism and fat homeostasis, with a particular focus on clinical outcomes associated with its increased secretion in the presence of adipose tissue accumulation and dysfunction