Molecular mechanisms of metabolic associated fatty liver disease (MAFLD): functional analysis of lipid metabolism pathways

Abstract

The metabolic-associated fatty liver disease (MAFLD) is a condition of fat accumulation in the liver in combination with metabolic dysfunction in the form of overweight or obesity and insulin resistance. It is also associated with an increased cardiovascular disease risk, including hypertension and atherosclerosis. Hepatic lipid metabolism is regulated by a combination of the uptake and export of fatty acids, de novo lipogenesis, and fat utilization by β-oxidation. When the balance between these pathways is altered, hepatic lipid accumulation commences, and long-term activation of inflammatory and fibrotic pathways can progress to worsen the liver disease. This review discusses the details of the molecular mechanisms regulating hepatic lipids and the emerging therapies targeting these pathways as potential future treatments for MAFLD.

Keywords: hepatic steatosis; intracellular signaling; non alcoholic fatty liver disease; obesity.

Figure 1. MAFLD grade of liver disease and fat content

Figure 2. Liver enzymes levels in MAFLD and metabolically fit livers

The plasma levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) liver biomarker enzymes and bilirubin are typically used in clinics to measure the level of liver dysfunction. The level of de novo lipogenesis and β-oxidation are essential to regulating the liver fat content.

Figure 3. Pathways governing lipid accumulation in the liver

Fatty acid uptake and de novo lipogenesis can be up-regulated in MAFLD (green arrows), while fatty acid export and oxidation of fatty acids by the mitochondria and peroxisomes are decreased in MAFLD (red arrows); ACC, acetyl-CoA carboxylase; DAG, diacylglycerol; FAS, fatty acid synthase; SCD1, stearoyl-CoA desaturase-1; VLDL, very-low-density lipoprotein. Created with Biorender.com

Figure 4. Mechanism of hepatic stellate cell activation

Both adipose tissue inflammation and gut dysbiosis can contribute to hepatocyte steatosis. Hepatocyte steatosis increases endoplasmic reticulum (ER) stress and mitochondrial ROS production, which alters hepatic cytokines resulting in stellate cell activation. Hepatic steatosis and gut dysbiosis also lead to the activation of hepatic macrophages and Kupffer cells that further activates stellate cells to increase collagen synthesis resulting in fibrosis and inflammation and promoting NASH; CCL3/5, chemokine (C-C motif) ligands 3/5; ER, endoplasmic reticulum; IL-1β, interleukin 1β; MCP1, monocyte chemoattractant protein-1; NASH, non-alcoholic steatohepatitis; ROS, reactive oxygen species; TGFβ, transforming growth factor-β. Created with Biorender.com

Figure 5. Influence of current and emerging therapies on MAFLD

Risk factors such as obesity, diet, diabetes mellitus, dyslipidemia, oxidative stress, inflammation, and apoptosis stimulate MAFLD, which can progress to liver fibrosis, cirrhosis, and hepatocellular carcinoma. Lifestyle intervention (diet and exercise) and therapeutic interventions inhibit fatty liver diseases; ARB, angiotensin receptor blocker; DPP-4, dipeptidyl peptidase-4; FGF, fibroblast growth factor; GLP-1RAs, glucagon-like peptide-1 receptor agonists; PPAR, peroxisome proliferator-activated receptor; SGLT-2, sodium-glucose cotransporter-2; THR-β, thyroid hormone receptor-β. Created with Biorender.com