Developmental origins of NAFLD: a womb with a clue

Abstract

Changes in the maternal environment leading to an altered intrauterine milieu can result in subtle insults to the fetus, promoting increased lifetime disease risk and/or disease acceleration in childhood and later in life. Particularly worrisome is that the prevalence of NAFLD is rapidly increasing among children and adults, and is being diagnosed at increasingly younger ages, pointing towards an early-life origin. A wealth of evidence, in humans and non-human primates, suggests that maternal nutrition affects the placenta and fetal tissues, leading to persistent changes in hepatic metabolism, mitochondrial function, the intestinal microbiota, liver macrophage activation and susceptibility to NASH postnatally. Deleterious exposures in utero include fetal hypoxia, increased nutrient supply, inflammation and altered gut microbiota that might produce metabolic clues, including fatty acids, metabolites, endotoxins, bile acids and cytokines, which prime the infant liver for NAFLD in a persistent manner and increase susceptibility to NASH. Mechanistic links to early disease pathways might involve shifts in lipid metabolism, mitochondrial dysfunction, pioneering gut microorganisms, macrophage programming and epigenetic changes that alter the liver microenvironment, favouring liver injury. In this Review, we discuss how maternal, fetal, neonatal and infant exposures provide developmental clues and mechanisms to help explain NAFLD acceleration and increased disease prevalence. Mechanisms identified in clinical and preclinical models suggest important opportunities for prevention and intervention that could slow down the growing epidemic of NAFLD in the next generation.

Figure 1. Early in utero factors programming NAFLD

During pregnancy, mothers chronically consuming a high-fat or Western-style diet might be obese and insulin resistant, with increased plasma lipid and glucose levels that are transferred via the placenta to the fetus. Maternal insulin resistance and hyperinsulinaemia might additionally impair placenta function, reducing blood flow and decreasing fetal oxygen delivery, resulting in fetal hypoxia. Evidence also exists for increased inflammation and cytokine production in the placenta. Collectively, these exposures to the fetus comprise early factors that promote a pathological offspring phenotype. GDM, gestational diabetes; HFD, high-fat diet; ROS, reactive oxygen species; WSD, Western-style diet.

Figure 2. Postnatal events contributing to steatosis and progression to NASH

Steatosis is present in the fetal liver in offspring from obese pregnancies and remains evident in the neonatal liver. Additional early insults after birth in these offspring include exposures from breast milk, microbiota, maturation of immune pathways, inflammation and impaired mitochondrial function. Each of these exposures furthers the progression of fatty liver disease. Across the lifespan, continued exposure to an unhealthy diet after weaning can represent a ‘second hit’ that accelerates the liver phenotype towards development of NASH.

Figure 3. Early liver microenvironment influences macrophage programming

The prenatal and perinatal liver microenvironment in the offspring of mothers with obesity promotes programming of liver macrophages (recruited and resident) via metabolic and epigenetic alterations, favouring a profibrotic phenotype and expression of pro-inflammatory molecules upon a second postnatal ‘hit’. This maladaptive immunity might directly result from alterations in the infant gut–liver axis associated with dysbiosis owing to perinatal colonization of the infant intestine with microbiota from a mother with obesity, and postnatal compromise of the intestinal barrier leading to altered absorption of endotoxins, cytokines, bile acids, SCFAs, metabolites and hormones. Disturbances in macrophage function can lead to aberrant tissue repair, such that uncontrolled production of inflammatory mediators and growth factors, deficient generation of anti-inflammatory macrophages or failed communication between macrophages and stellate cells contributes to persistent liver injury and the development of pathological fibrosis. Arg1, arginase 1; FGF19, fibroblast growth factor 19 (also known as FGF15 in mice); FSP1, fibroblast-specific protein 1 (also known as S100-A4); FXR, farnesoid X receptor (also known as bile acid receptor); HIF1, hypoxia-inducible factor 1; MMP, matrix metalloproteinase; SCFA, short-chain fatty acid; TGFβ, transforming growth factor β; TGR5, G protein-coupled bile acid receptor 1; TIMP, tissue inhibitor of matrix metalloproteinase (also known as Metalloproteinase inhibitor 1); TLR, Toll-like receptor.