Nonalcoholic fatty liver disease and type 2 diabetes: pathophysiological mechanisms shared between the two faces of the same coin

Abstract

The pathophysiological mechanisms underlying the close relationship between nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes mellitus (T2DM) are multiple, complex and only partially known. The purpose of this paper was to review the current knowledge of these mechanisms in a unified manner. Subjects with NAFLD and T2DM have established insulin resistance (IR), which exacerbates the two comorbidities. IR worsens NAFLD by increasing the accumulation of free fatty acids (FFAs) in the liver. This occurs due to an increase in the influx of FFAs from peripheral adipose tissue by the activation of hormone-sensitive lipase. In addition, there is de novo increased lipogenesis, a transcription factor, the sterols regulatory element-binding transcription factor 1c (SREBP-1c), which activates the expression of several genes strongly promotes lipogenesis by the liver and facilitate storage of triglycerides. Lipids accumulation in the liver induces a chronic stress in the endoplasmic reticulum of the hepatocytes. Genome-wide association studies have identified genetic variants associated with NAFLD severity, but unrelated to IR. In particular, the alteration of patatin-like phospholipase domain-containing protein 3 contributes to the susceptibility to NAFLD. Furthermore, the lipotoxicity of ceramides and diacylglycerol, well known in T2DM, triggers a chronic inflammatory process favoring the progression from hepatic steatosis to steatohepatitis. Reactive oxygen species produced by mitochondrial dysfunction trigger both liver inflammation and beta-cells damage, promoting the progression of both NAFLD and T2DM. The close association between NAFLD and T2DM is bidirectional, as T2DM may trigger both NAFLD onset and its progression, but NAFLD itself may contribute to the development of IR and T2DM. Future studies on the mechanisms will have to deepen the knowledge of the interaction between the two pathologies and should allow the identification of new therapeutic targets for the treatment of NAFLD, currently substantially absent.

Pathophysiological mechanisms and clinical evidence of relationship between Nonalcoholic fatty liver disease (NAFLD) and cardiovascular disease

“…NAFLD is characterized by a large spectrum of disorders, ranging from simple steatosis to non-alcoholic steatohepatitis, which both in turn may progress into overt cirrhosis and hepatocellular carcinoma [12][13][14]. NAFLD diagnosis can be performed only in absence of other causes of chronic liver disease such as alcohol consumption (<30 g/day for men and <20 g/day for women), congenital or autoimmune diseases, viruses, and iatrogenic injury [15].…”

Mechanisms of Non-Alcoholic Fatty Liver Disease in the Metabolic Syndrome. A Narrative Review

“…Along with IR, also genetic and epigenetic factors, diet, lifestyle, mitochondrial dysfunction, low degree chronic inflammation, adipose tissue dysfunction, oxidative stress and of endoplasmic reticulum (ER), microbiota and constitutive immunity may be involved [ 15 ]. These elements, identified under a complex theory named the “multiple parallel hits hypothesis” [ 16 ], act in a convergent and synergic way in the hepatocyte, thus inducing the damage.…”

Associations between serum biomarkers and non-alcoholic liver disease: Results of a clinical study of Mediterranean patients with obesity

“…Hepatic steatosis and steatohepatitis are promoted by the lipotoxicity of ceramides and diacylglycerol, a condition that is well documented in T2DM. Reactive oxygen species generated by mitochondrial malfunction cause beta-cell destruction and hepatic inflammation, accelerating the development of both NAFLD and T2DM ( 33 ). On the other hand, the NAFLD pathophysiology also leads to changes in the hepatic secretion of proteins, lipids, other metabolites, and miRNAs, which may disrupt the liver, muscle, adipose tissue, and pancreatic metabolism, thus promoting insulin resistance ( 34 ).…”