Detangling the interrelations between MAFLD, insulin resistance, and key hormones

Abstract

Metabolic dysfunction–associated fatty liver disease (MAFLD) has increasingly become a significant and highly prevalent cause of chronic liver disease, displaying a wide array of risk factors and pathophysiologic mechanisms of which only a few have so far been clearly elucidated. A bidirectional interaction between hormonal discrepancies and metabolic-related disorders, including obesity, type 2 diabetes mellitus (T2DM), and polycystic ovarian syndrome (PCOS) has been described. Since the change in nomenclature from non-alcoholic fatty liver disease (NAFLD) to MAFLD is based on the clear impact of metabolic elements on the disease, the reciprocal interactions of hormones such as insulin, adipokines (leptin and adiponectin), and estrogens have strongly pointed to the intrinsic links that lead to the heterogeneous epidemiology, clinical presentations, and risk factors involved in MAFLD in different populations. The objective of this work is twofold. Firstly, there is a brief discussion regarding the change in nomenclature as well as epidemiology, risk factors, and pathophysiologic mechanisms other than hormonal effects, which include nutrition and the gut microbiome, as well as genetic and epigenetic influences. Secondly, we review the basis of the most important hormonal factors involved in the development and progression of MAFLD that act both independently and in an interrelated manner.

Screening for MAFLD: who, when and how?

“…22 The mechanism has been discovered to a certain degree, finding that by acting through the oestrogen receptors (ERs) ERα, ERβ and GPER (G-protein-coupled oestrogen receptor), oestrogens limit dietary-induced de novo lipogenesis (DNL) and reduce free fatty acid (FFA) uptake, thus restricting the influx of these into the liver, decreasing steatosis development in the liver. 23 Furthermore, increased oestrogen supplementation in rats was shown to decrease the hepatic expression of lipogenic enzyme synthesis through decreased hepatic expression of SREBP-1c. 24,25 Based on the mentioned facts, men and women in lower oestrogen states would have increased risk and therefore more reason for MAFLD screening, when evaluated with other risk factors.…”

Discovery of the First-in-Class Intestinal Restricted FXR and FABP1 Dual Modulator ZLY28 for the Treatment of Nonalcoholic Fatty Liver Disease

“…3−5 Previous studies suggested that many metabolic diseases are the risk factors of NAFLD, including type 2 diabetes, obesity, dyslipidemia, and hypertension. 6,7 The latest statistics indicated that NAFLD affects 1 billion people worldwide, 8 and patients with NASH have a greater risk of progressing to cirrhosis, liver cancer, or liver-related death. 9 NAFLD has become a global health issue in the past decades, but no drug has yet been approved in this area.…”

“…Nonalcoholic fatty liver disease (NAFLD), characterized by excessive accumulation of fat in hepatocytes, , is a common chronic liver disease including a wide spectrum of disorders ranging from nonalcoholic fatty liver (NAFL) to nonalcoholic steatohepatitis (NASH) and cirrhosis. − Previous studies suggested that many metabolic diseases are the risk factors of NAFLD, including type 2 diabetes, obesity, dyslipidemia, and hypertension. , The latest statistics indicated that NAFLD affects 1 billion people worldwide, and patients with NASH have a greater risk of progressing to cirrhosis, liver cancer, or liver-related death . NAFLD has become a global health issue in the past decades, but no drug has yet been approved in this area.…”

Editorial: Treatment with Dual Incretin Receptor Agonists to Maintain Normal Glucose Levels May Also Maintain Normal Weight and Control Metabolic Dysfunction-Associated Fatty Liver Disease (MAFLD)

“…The global prevalence of MAFLD is 30.4% in the general population and up to 80% in patients with type 2 diabetes mellitus (T2DM) or obesity [ 1 ]. MAFLD is associated with insulin resistance, T2DM, obesity, hypertension, and atherogenic dyslipidemia [ 2 , 3 ]. Insulin resistance is the key risk factor for the development and progression of MAFLD [ 2 , 3 ].…”

“…MAFLD is associated with insulin resistance, T2DM, obesity, hypertension, and atherogenic dyslipidemia [ 2 , 3 ]. Insulin resistance is the key risk factor for the development and progression of MAFLD [ 2 , 3 ]. Since 2020 an international consensus has proposed the term, MAFLD, to describe the presence of hepatic steatosis with one or more of the following: overweight/obesity, T2DM, or evidence of two or more features of metabolic dysfunction in patients of normal weight [ 4 , 5 ].…”