Identify Liver Disease in 70% of Type 2 Diabetics

Metabolic dysfunction–associated steatotic liver disease (MASLD) is defined as the presence of excess hepatic triglycerides on imaging (for example, >5.6% volume using proton density fat fraction with magnetic resonance spectroscopy) or histology with at least one feature of the metabolic syndrome, including obesity or type 2 diabetes in the absence of excess alcohol intake or other chronic liver disease (1). This condition affects a third of the global adult population and up to 70% of individuals living with type 2 diabetes (1). It is a silent pandemic; as few as 5% of the individuals affected are aware of the disease (2), and there is considerable clinical inertia with regard to diagnosis and management among non-hepatologists (3). Hepatic inflammation and fibrosis develop in approximately 20%–30% of people with MASLD, a condition called metabolic dysfunction–associated steatohepatitis (MASH), and this leads to a dramatic increase in morbidities and mortalities including liver failure, hepatocarcinoma, cardiovascular diseases, cognitive decline, and chronic kidney diseases (1). Therefore, understanding the mechanisms that lead to the transition from MASLD to MASH is critical to identify new therapeutic targets that may maximize therapeutic benefits.

Hepatocytes, hepatic stellate cells (HSCs), and liver macrophages operate in a finely tuned and spatially coordinated network to support metabolic homeostasis (4). In the healthy liver, changes in hepatocellular lipid acquisition from fatty acid uptake and de novo lipogenesis (DNL) are balanced with lipid consumption and storage from fatty acid oxidation and very low-density lipoprotein (VLDL) export, respectively, over fasting and feeding periods throughout the day (Figure 1). Hepatocytes, comprising about 70%–80% of liver volume, carry out critical metabolic functions including gluconeogenesis and lipid and cholesterol metabolism. Kupffer cells, the resident embryonically derived liver macrophages, continuously sample portal blood for microbial components and debris, playing a crucial role in immune surveillance and clearance of gut-derived antigens (5, 6). They also contribute to immune tolerance and support hepatocyte function through clearance of senescent cells and orchestration of early responses to tissue injury (6). Macrophages and hepatocytes interact closely with HSCs, which, in addition to vitamin A storage, play several essential roles in maintaining liver structure and function by regulating sinusoidal blood flow through contractile responses and contributing to the homeostatic turnover of extracellular matrix (ECM) components (7, 8). Under most homeostatic conditions, hepatocytes, Kupffer cells, and HSCs primarily rely on mitochondrial oxidative phosphorylation and fatty acid metabolism to support their physiological roles (4–6).

The stability of this homeostatic network is highly susceptible to chronic metabolic perturbation, and in the context of sustained overnutrition, hepatocyte lipid handling becomes dysregulated. This results in the accumulation of triglycerides and, more importantly, toxic lipid and metabolic intermediates that can be primarily attributed to defects in four interrelated pathways: (a) increased uptake of fatty acids from extrahepatic sources including diet and adipose tissue; (b) increased DNL; (c) reduced fatty acid oxidation; and (d) impaired VLDL production. While recent studies have highlighted how VLDL production impacts the risk of liver damage versus cardiovascular complications in people with MASLD (9), we will not focus on this topic, in order to concentrate on interactions with the first three variables. Importantly, with the accumulation of lipotoxic and metabolic intermediates in the liver, there is recruitment and differentiation of bone marrow–derived monocytes that give rise to monocyte-derived macrophages (10–13), which express TREM2 and are commonly referred to as lipid-associated macrophages (14), and/or scar-associated macrophages (15). Steatotic hepatocytes and activated immune cells also trigger a phenotypic shift in HSCs marked by loss of lipid droplets and increased glycolysis, leading to proliferation and transdifferentiation into fibrogenic myofibroblasts that are characterized by a contractile, ECM-producing phenotype (4–6). These changes in hepatocyte, macrophage, and HSC identity and function reinforce a feed-forward cycle of metabolic stress, inflammation, and tissue remodeling that characterize the development of MASH and fibrosis.

In this Review we aim to describe in an integrative manner how the metabolic pathways of fatty acid uptake, DNL, and fatty acid oxidation are tightly interconnected and not only contribute to hepatic steatosis but also generate metabolic intermediates that activate HSCs and macrophages to promote MASH and fibrosis.