Emerging therapeutic approaches for the treatment of NAFLD and type 2 diabetes mellitus

Abstract

Non-alcoholic fatty liver disease (NAFLD) has emerged as the most prevalent liver disease in the world, yet there are still no approved pharmacological therapies to prevent or treat this condition. NAFLD encompasses a spectrum of severity, ranging from simple steatosis to non-alcoholic steatohepatitis (NASH). Although NASH is linked to an increased risk of hepatocellular carcinoma and cirrhosis and has now become the leading cause of liver failure-related transplantation, the majority of patients with NASH will ultimately die as a result of complications of type 2 diabetes mellitus (T2DM) and cardiometabolic diseases. Importantly, NAFLD is closely linked to obesity and tightly interrelated with insulin resistance and T2DM. Thus, targeting these interconnected conditions and taking a holistic attitude to the treatment of metabolic disease could prove to be a very beneficial approach. This Review will explore the latest relevant literature and discuss the ongoing therapeutic options for NAFLD focused on targeting intermediary metabolism, insulin resistance and T2DM to remedy the global health burden of these diseases.

Fig. 1 |. The pathological spectrum of NAFLD.

The excess accumulation of liver lipids, mostly in the form of triglycerides, is referred to as steatosis, which is defined as the presence of >5% lipid accumulation within hepatocytes. It is estimated that approximately 25% of the global population has some form of non-alcoholic fatty liver disease (NAFLD). Eventually, excess lipid accumulation might overwhelm the liver’s capacity for the proper storage or disposal of fatty acids, leading to the generation of toxic lipid species. Lipotoxicity might produce endoplasmic reticulum stress, oxidative stress and mitochondrial dysfunction, resulting in inflammation and hepatocyte degeneration (ballooning), which are the defining characteristics of non-alcoholic steatohepatitis (NASH). NASH is estimated to be present in up to 60% of patients with NAFLD who have undergone a liver biopsy. Over time, hepatocyte death, inflammation and immune cell activation might promote hepatic stellate cell activation. Stellate cells differentiate into fibrogenic myofibroblasts that migrate to sites of hepatic injury and are the major drivers of fibrosis. Detectable fibrosis is present in approximately 41% of patients with NASH and 22% of individuals with advanced fibrosis go on to develop hepatic scarring, referred to as cirrhosis. Lastly, ~2% of patients with cirrhosis will probably develop hepatocellular carcinoma (HCC) within 3 years. Percentages in the figure are representative of the proportion of the subpopulation that will probably present or progress to more advanced liver disease.

Fig. 2 |. Role of insulin resistance in NAFLD.

a | Insulin resistance occurs when tissues inadequately respond to the hormone insulin. In adipose tissue, the normal ability of insulin to suppress lipolysis is impaired, resulting in the excess release of free fatty acids, which are subsequently taken up by the liver in addition to fat obtained from the diet^–. The inability of tissues to properly respond to insulin results in abnormally elevated glucose levels (hyperglycaemia), which leads to the production and secretion of surplus insulin levels to those needed to maintain blood levels of glucose (hyperinsulinaemia). Both hyperglycaemia and hyperlipidaemia stimulate de novo lipogenesis (DNL), which further elevates hepatic lipid accumulation^,. Normally, appropriate hepatic levels of lipids would be maintained by their increased export through lipoprotein secretion; however, lipoprotein secretion is not adequately elevated in non-alcoholic fatty liver disease (NAFLD). b | NAFLD is also linked to several extrahepatic comorbidities. Patients with NAFLD have an increased risk of developing type 2 diabetes mellitus (T2DM) and cardiovascular disease (CVD). In addition, T2DM is an independent risk factor for NAFLD^, and is also correlated with an increased risk of heart disease. Lastly, NAFLD is associated with an elevated risk of developing chronic kidney disease (CKD), which is also highly correlated to T2DM and CVD.

Fig. 3 |. Targeting of intermediary metabolism for NAFLD therapy.

Mechanistic illustration of investigational drugs currently in clinical trials. Inhibitors of ketohexokinase block the rate-limiting step of fructose metabolism, an inducer of de novo lipogenesis. Mitochondrial pyruvate carrier (MPC) inhibitors act downstream to prevent the import of pyruvate into the mitochondria, where it can be metabolized to intermediates that are used for gluconeogenesis (OAA) or fatty acid synthesis (citrate)^,. Lastly, several inhibitors are being investigated that target various enzymes (such as ACC, FAS, SCD1 and DGAT2) involved in the synthesis of triglycerides. ACC, acetyl-CoA carboxylase; DAG, diacylglycerol; DGAT2, diacylglycerol acyltransferase 2; F-1-P, fructose-1-phosphate; FAO, fatty acid oxidation; FAS, fatty acid synthase; MUFA, monounsaturated fatty acid; OAA, oxaloacetate; SCD1, stearoyl-CoA desaturase 1; SFA, saturated fatty acid; TCA, tricarboxylic acid cycle.