Role of Insulin Resistance in MAFLD

Abstract

Many studies have reported that metabolic dysfunction is closely involved in the complex mechanism underlying the development of non-alcoholic fatty liver disease (NAFLD), which has prompted a movement to consider renaming NAFLD as metabolic dysfunction-associated fatty liver disease (MAFLD). Metabolic dysfunction in this context encompasses obesity, type 2 diabetes mellitus, hypertension, dyslipidemia, and metabolic syndrome, with insulin resistance as the common underlying pathophysiology. Imbalance between energy intake and expenditure results in insulin resistance in various tissues and alteration of the gut microbiota, resulting in fat accumulation in the liver. The role of genetics has also been revealed in hepatic fat accumulation and fibrosis. In the process of fat accumulation in the liver, intracellular damage as well as hepatic insulin resistance further potentiates inflammation, fibrosis, and carcinogenesis. Increased lipogenic substrate supply from other tissues, hepatic zonation of Irs1, and other factors, including ER stress, play crucial roles in increased hepatic de novo lipogenesis in MAFLD with hepatic insulin resistance. Herein, we provide an overview of the factors contributing to and the role of systemic and local insulin resistance in the development and progression of MAFLD.

Keywords: MAFLD; NAFLD; de novo lipogenesis (DNL); diacylglycerol (DAG); insulin resistance; insulin signaling; lipid metabolism; triglycerides (TG).

Figure 1

Summary of genetic variants related to the pathogenesis of NAFLD. Many genome-wide association studies have identified novel loci associated with disease severity phenotypes of NAFLD. The PNPLA3 (rs738409 C>G) variant, which causes impaired mobilization of TG from lipid droplets, predisposes to progression along the full spectrum of liver damage associated with fatty liver. The TM6SF2 (rs58542926 C>T) variant, a loss-of-function variant, is associated with hepatic steatosis via decreased VLDL-TG secretion in the liver. The MBOAT7 (rs641738 C>T) variant, resulting in lower MBOAT7 protein expression in the liver, is associated with increased hepatic fat content through inducing changes in the remodeling of phospholipids. In addition, other genetic variants known to be involved in the regulation of lipid metabolism (LYPLAL1, APOB, MTP, LPIN1, UCP2), glucose metabolism and lipogenesis (GCKR), innate immunity (IL28B, MERTK), insulin signaling (ENPP1, IRS1), oxidative stress (SOD2), and fibrogenesis (KLF6) have also been reported to be associated with the progression of NAFLD.

Figure 2

Summary of factors involved in the pathogenesis of MAFLD. Imbalance between energy intake and expenditure leads to fat accumulation in adipose tissue. When the accumulation exceeds the capacity for adipose tissue remodeling, increased release of FFAs and proinflammatory cytokines with dysregulated production of adipokines results in the development of insulin resistance in the skeletal muscle as well as adipose tissue. Glucose and FFAs not utilized in the skeletal muscle and adipose tissue become substrates for hepatic DNL. Increased uptake of FFAs and relatively decreased VLDL-TG secretion also promote hepatic fat accumulation. Compensatory increase in FFA oxidation is accompanied by enhanced oxidative stress and inflammation. Dysbiosis, defined as an imbalance in the microbiota composition, can disrupt the tight junctions in intestinal endothelial cells, leading to increased mucosal permeability and translocation of bacterial LPS from bacteria. Small intestinal bacterial overgrowth and gut-derived metabolites, such as endogenous ethanol, are also associated with the progression of MAFLD. In addition, people with specific genetic risk variants are also susceptible to the development and progression of MAFLD. Taken together, insulin resistance in adipose tissue and the skeletal muscle, dysbiosis, and genetic predisposition are synergistically involved in fat accumulation and inflammation in the liver, followed by subsequent fibrosis and carcinogenesis, in patients with MAFLD.

Figure 3

After insulin binds to the insulin receptor, autophosphorylation of tyrosine residues in the intracellular subunit of each of the receptors causes docking and phosphorylation of Irs1/Irs2, followed by activation of the downstream kinase cascades, such as the PI3K/Akt pathway. For induction of SREBP1c, mTORC1 activation and concomitant inhibition of FoxO1 via the PI3K/Akt pathway are required. In addition to the DAG-PKCε pathway inhibiting physiological phosphorylation of the insulin receptor, hyperinsulinemia leads to downregulation of hepatic Irs2 expression, resulting in the progression of hepatic insulin resistance. GLUT2 is the major glucose transporter in hepatocytes. In response to an increase in the intracellular glucose concentration, ChREBP induces expression of various genes related to lipogenic enzymes, independent of insulin signaling. Due to elevated Irs1 expression in the perivenous (PV) zone, which is the primary site of lipogenesis, insulin signaling is rather enhanced in the presence of hyperinsulinemia despite the downregulation of Irs2, resulting in increased lipogenesis and development of steatosis. Independent of insulin signaling, ER stress also activates SREBP through increased cleavage of S1P by caspase-2.