Excessive early-life cholesterol exposure may have later-life consequences for nonalcoholic fatty liver disease

Introduction

The developmental origins of health and disease postulates that early-life environmental exposures, including over and under-nutrition, influence both in utero and early postnatal development to alter the trajectory of disease risk in adulthood.¹ The in utero and postnatal environments are recognized as critical windows of developmental plasticity where offspring are highly susceptible to changes in the maternal metabolic milieu.^1–3 One of the earliest recognitions of a link between early-life nutrient exposure and the later development of noncommunicable diseases was the Thrifty Gene Hypothesis established by Hales and Barker.⁴ In this paradigm, nutrient restriction during gestation was hypothesized to program offspring metabolism to preferentially favor a nutrient restrictive postnatal environment. Alternatively, “mismatch” to an energy-rich postnatal environment was hypothesized to lead to metabolic adaptations that would increase susceptibility to chronic disease risk. Perhaps more pertinent to a “western” lifestyle of excess nutrient, there is also ample evidence that supports a “second hit” hypothesis whereby early-life exposure to an energy-rich environment (e.g., maternal obesity) followed by consumption of a postnatal energy-rich diet would also lead to metabolic adjustments that favor disease predisposition in adulthood.³

Nonalcoholic fatty liver disease (NAFLD) is the most prevalent form of chronic liver disease among pediatric and adult populations.^5,6 NAFLD is traditionally thought to be the hepatic manifestation of metabolic syndrome⁷ resulting in impaired metabolic function characterized by insulin resistance, deposition of hepatic free fatty acids (FFAs), increased de novo lipogenesis, and dysregulated triglyceride (TG) and very low-density lipoprotein (VLDL) production and secretion.^5,8,9 Although hypercholesterolemia is typically associated with cardiovascular disease (CVD), it is also strongly associated with NAFLD and progression to nonalcoholic steatohepatitis (NASH).^10–12

Although the origins of NAFLD are often attributed to lifestyle factors (e.g., lack of exercise and poor diet), the alarming rise in pediatric NAFLD suggests that metabolic abnormalities experienced in utero and in the immediate postnatal life may program liver dysfunction in developing offspring.¹³ Previous human reports have linked infant hepatic fat accumulation with gestational diabetes^14,15 and maternal obesity^16,17; however, there is little evidence linking maternal hypercholesterolemia (MHC) to NAFLD in human offspring. Alternatively, data from a range of animal models support a role for excessive early cholesterol exposure in NAFLD development. Therefore, drawing largely...