The Interconnection between Hepatic Insulin Resistance and Metabolic Dysfunction-Associated Steatotic Liver Disease—The Transition from an Adipocentric to Liver-Centric Approach

Abstract

The central mechanism involved in the pathogenesis of MAFLD is insulin resistance with hyperinsulinemia, which stimulates triglyceride synthesis and accumulation in the liver. On the other side, triglyceride and free fatty acid accumulation in hepatocytes promotes insulin resistance via oxidative stress, endoplasmic reticulum stress, lipotoxicity, and the increased secretion of hepatokines. Cytokines and adipokines cause insulin resistance, thus promoting lipolysis in adipose tissue and ectopic fat deposition in the muscles and liver. Free fatty acids along with cytokines and adipokines contribute to insulin resistance in the liver via the activation of numerous signaling pathways. The secretion of hepatokines, hormone-like proteins, primarily by hepatocytes is disturbed and impairs signaling pathways, causing metabolic dysregulation in the liver. ER stress and unfolded protein response play significant roles in insulin resistance aggravation through the activation of apoptosis, inflammatory response, and insulin signaling impairment mediated via IRE1/PERK/ATF6 signaling pathways and the upregulation of SREBP 1c. Circadian rhythm derangement and biological clock desynchronization are related to metabolic disorders, insulin resistance, and NAFLD, suggesting clock genes as a potential target for new therapeutic strategies. This review aims to summarize the mechanisms of hepatic insulin resistance involved in NAFLD development and progression.

The clinician's view on the advantages and contradictions of the new nomenclature of steatotic liver disease: A review

“…Предложенный подход основывался на том факте, что NAFLD является главным образом следствием системной метаболической дисфункции, в частности наличия МС [1,3,[18][19][20][21]. Другим обстоятельством, которое необходимо учитывать при обсуждении данной нозологии, представляется многофакторность этиопатогенеза, который включает особенности питания и потребления алкоголя, нарушение целостности кишечного барьера и особенности микробиоты кишечника, дисфункцию субклеточных структур (митохондрий, эндоплазматического ретикулума), а также нарушение обмена веществ и/или гормональные расстройства [20,[22][23][24][25][26][27]. Выдвинуты предложения по изменению термина NAFLD с заменой определения «неалкогольная» на один из вариантов, указывающих на основной вклад в поражение печени одного из перечисленных факторов патогенеза [28,29].…”

Underlying Mechanisms behind the Brain–Gut–Liver Axis and Metabolic-Associated Fatty Liver Disease (MAFLD): An Update

“…Furthermore, the expression of serum exosomal miRNAs can aid in detecting MALFD. Changes in the levels of liver enzymes, such as alanine transaminase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), and Gamma Glutamyl Transpeptidase (GGT), are important not only for the differential diagnosis of liver disease but also for evaluating the severity of the disease [15,136,140].…”

“…This complex network involves the neural, endocrine, and immune systems [13][14][15][16][17]. The intricate information exchanged between the CNS and the gut microbiome is mediated by microbiome-derived products, including serotonin, dopamine, norepinephrine, shortchain fatty acids (SCFAs), glutamate, γ-aminobutyric acid (GABA), secondary bile acids, tryptophan metabolites, and histamine.…”

“…Thus, a challenge in diagnosing MAFLD is to determine if metabolic syndrome leads to a deficit in the production of adipose tissue hormones. For example, gut peptides such as ghrelin, cholecystokinin (CCK), and GLP-1 may activate the afferent vagus nerve and stimulate the CNS; such signs are integrated and, subsequently, regulate food intake and the metabolism of liver glycolipids through a negative feedback cycle [15,21,26,30,35].…”

Normal triglyceride concentration and the risk of diabetes mellitus type 2 in the general population of China

“…In addition, research suggests that high triglyceride levels increase the risk of insulin resistance, as they can lead to fat accumulation in the liver and muscles. This accumulation triggers insulin resistance and affects the secretion of adipokines, thereby further impacting insulin signaling and glucose uptake ( 13 ). This close association between triglyceride levels and the development of diabetes highlights the importance of triglycerides as a biomarker for assessing the risk of diabetes.…”