Insulin resistance associates with hepatic lobular inflammation in subjects with obesity

Abstract

Purpose Obese subjects with nonalcoholic fatty liver disease (NAFLD) are more prone to develop additional metabolic disturbances such as systemic insulin resistance (IR) and type 2 diabetes. NAFLD is defined by hepatic steatosis, lobular inflammation, ballooning and stage of fibrosis, but it is unclear if and which components could contribute to IR. Objective To assess which histological components of NAFLD associate with IR in subjects with obesity, and if so, to what extent. Methods This cross-sectional study included 78 obese subjects (mean age 46 ± 11 years; BMI 42.2 ± 4.7 kg/m2). Glucose levels were analysed by hexokinase method and insulin levels with electrochemiluminescence. Homeostasis model assessment-estimated insulin resistance (HOMA-IR) was calculated. Liver biopsies were evaluated for histological components of NAFLD. Results A positive association between overall NAFLD Activity Score and HOMA-IR was found (r s = 0.259, P = 0.022). As per individual components, lobular inflammation and fibrosis stage were positively associated with HOMA-IR, glucose and insulin levels (P < 0.05), and HOMA-IR was higher in patients with more inflammatory foci or higher stage of fibrosis. These findings were independent of age, BMI, triglyceride levels, diabetes status and sex (all P < 0.043). In a combined model, lobular inflammation, but not fibrosis, remained associated with HOMA-IR. Conclusion In this group of obese subjects, a major contributing histological component of NAFLD to the relation between NAFLD severity and IR seems to be the grade of hepatic lobular inflammation. Although no causal relationship was assessed, preventing or mitigating this inflammatory response in obesity might be of importance in controlling obesity-related metabolic disturbances.

The Endocannabinoid System in Pediatric Inflammatory and Immune Diseases

“…It has been observed that the CB2 Q63R variant is also present in subjects with NAFLD and is associated with high-grade inflammation in the liver [103]. Since CB1 and CB2 receptors are also expressed in this organ, their regulation could be important for reducing liver impairments, as demonstrated also by Coppola et al in patients with chronic hepatitis C (HCV) [103,104,105,106,107]. In collecting all of this evidence, it is possible to suggest the EC system as pathological marker and pharmacological target to manage, not only the obesity-associated inflammation, but also its secondary complications.…”

Improvement of Metabolic and Histological Changes of Adiposity in Rats by Synthetic Oleoyl Chalcones

“…The lipid aggregation in the adipose tissue up‐regulates the inflammatory cytokines, particularly the (TNF‐ α ) which triggers inflammation through the c‐Jun N ‐terminal kinase (JNK) and nuclear factor‐kappa B (NF‐κB) signaling pathways [12] . Overproduction of the TNF‐ α within the adipose tissue of obese rats not only induces lipogenesis and triglycerides accumulation but also, activates phosphorylation of the insulin receptor substrate‐1 (IRS‐1) initiating insulin resistance [13] …”

“…They suppress the sterol‐regulating element‐binding protein‐1 (SREBP‐1), stimulate the AMP‐activated protein kinase (AMPK), and peroxisome proliferator‐activated receptor alpha (PPAR‐ α ) triggering fatty acid oxidation and thus improving insulin sensitivity [13] …”

“…[12] Overproduction of the TNF-α within the adipose tissue of obese rats not only induces lipogenesis and triglycerides accumulation but also, activates phosphorylation of the insulin receptor substrate-1 (IRS-1) initiating insulin resistance. [13] Under healthy circumstances, the adipose tissue secretes adiponectin which is a circulating metabolic regulating protein hormone. These hormones regulate, glucose metabolism, fatty acid oxidation, and crucially they down-regulate TNF-α production.…”

“…[12] They suppress the sterol-regulating element-binding protein-1 (SREBP-1), stimulate the AMP-activated protein kinase (AMPK), and peroxisome proliferatoractivated receptor alpha (PPAR-α) triggering fatty acid oxidation and thus improving insulin sensitivity. [13] Just like that, adiponectin functions as endogenous hypolipidemic, anti-inflammatory factors, and hepaticprotective cytokines. Unfortunately, they are downregulated in hyperlipidemia.…”