Developmental origins of nonalcoholic fatty liver disease as a risk factor for exaggerated metabolic and cardiovascular-renal disease

Abstract

Intrauterine growth restriction (IUGR) is linked to increased risk for chronic disease. Placental ischemia and insufficiency in the mother are implicated in predisposing IUGR offspring to metabolic dysfunction, including hypertension, insulin resistance, abnormalities in glucose homeostasis, and nonalcoholic fatty liver disease (NAFLD). It is unclear whether these metabolic disturbances contribute to the developmental origins of exaggerated cardiovascular-renal disease (CVRD) risk accompanying IUGR. IUGR impacts the pancreas, adipose tissue, and liver, which are hypothesized to program for hepatic insulin resistance and subsequent NAFLD. NAFLD is projected to become the major cause of chronic liver disease and contributor to uncontrolled type 2 diabetes mellitus, which is a leading cause of chronic kidney disease. While NAFLD is increased in experimental models of IUGR, lacking is a full comprehension of the mechanisms responsible for programming of NAFLD and whether this potentiates susceptibility to liver injury. The use of well-established and clinically relevant rodent models, which mimic the clinical characteristics of IUGR, metabolic disturbances, and increased blood pressure in the offspring, will permit investigation into mechanisms linking adverse influences during early life and later chronic health. The purpose of this review is to propose mechanisms, including those proinflammatory in nature, whereby IUGR exacerbates the pathogenesis of NAFLD and how these adverse programmed outcomes contribute to exaggerated CVRD risk. Understanding the etiology of the developmental origins of chronic disease will allow investigators to uncover treatment strategies to intervene in the mother and her offspring to halt the increasing prevalence of metabolic dysfunction and CVRD.

Keywords: hypertension; inflammation; insulin resistance; placental ischemia; steatosis.

Fig. 1.

Reduced uterine perfusion pressure (RUPP) produces maternal hypertension (A), reduced placental weight (B), and reduced fetal weight (C) by gestational day (GD) 19. RUPP reduces birth weight in both male and female offspring (D). *P < 0.05 vs. normal pregnant; **P < 0.05 vs. corresponding control offspring of same sex from normal pregnant dams. [Panel A adapted from Alexander et al. (6) with permission from Wolters Kluwer Health Inc. Copyright © 2001 American Heart Association Inc.; panels B and C adapted from Spradley et al. (191) with permission from Wolters Kluwer Health, Inc. Copyright © 2016 American Heart Association, Inc.; panel D adapted from Intapad et al. (95) with permission from Wolters Kluwer Health, Inc. Copyright © 2015 American Heart Association, Inc.]

Fig. 2.

By 12 mo of age, male intrauterine growth restriction (IUGR) offspring from reduced uterine perfusion pressure (RUPP) pregnancies have elevated fasting glucose levels on normal chow diet. *P < 0.05 vs. control offspring from normal pregnant rats. [Adapted from Intapad et al. © 2017 (94), licensed under Creative Commons Attribution CC-BY 4.0.]

Fig. 3.

Hepatic protein expression of gluconeogenic factors in intrauterine growth restriction (IUGR) ewes at approximately gestation day (GD) 134, which were generated by exposing pregnant ewes to elevated ambient room temperature from approximately GD 38–120. Control fetuses were from pregnant ewes exposed to normal ambient temperatures. *P < 0.05 vs. control. [Adapted from Thorn et al. (203) with permission from Oxford University Press. Copyright © 2009 The Endocrine Society.]

Fig. 4.

Subcutaneous (SC) adipose tissue (A and B) and visceral adipose tissue (C and D) expression of lipogenic proteins acetyl-coenzyme A carboxylase (ACCα) and fatty acid synthase (FASN) in 6-mo-old intrauterine growth restriction (IUGR) male offspring produced by maternal protein restriction. *P < 0.05 vs. control offspring. [Adapted from Yee et al. (231) with permission from John Wiley and Sons. Copyright © American Oil Chemists' Society 2016 (AOCS).]

Fig. 5.

Steatotic grade (A) and plasma small dense LDL (B) and circulating markers of liver injury ALT (C) and AST (D) in male intrauterine growth restriction (IUGR) offspring from calorically-restricted (CR) pregnant C57Bl/6 mice. All offspring were on high-fat diet (60% lipids) from 9 to 22 wk treated with vehicle or the endoplasmic reticulum stress inhibitor tauroursodeoxycholic acid (TUDCA; 0.5 g·kg⁻¹·day⁻¹). *P < 0.05 vs. vehicle-treated control rats from ad libitum dams; **P < 0.05 vs. TUDCA-treated control rats. #P < 0.05 vs. vehicle-treated controls. [Adapted from Muramatsu-Kato et al. (152), licensed under Creative Commons Attribution CC-BY 4.0.]

Fig. 6.

Expression of proteins associated with activation of autophagy in liver tissue from newborn piglets with intrauterine growth restriction (IUGR). A: mammalian target of rapamycin. B: catalytic subunit of protein phosphatase 2A (PP2Ac). C: microtubule-associated protein 1A/1B-light chain 3 (LC3). D: autophagic vacuoles detected by electron microscopy. *P < 0.05 vs. control, normal-birthweight piglets. [Adapted from Long et al. (126) with permission from American Chemical Society. Copyright © 2016, American Chemical Society.]

Fig. 7.

Overall hypothetical scheme summarizing the integrative proposal that placental insufficiency and intrauterine growth restriction (IUGR) increases the risk for the development of metabolic dysfunction and exaggerated cardiovascular-renal disease (CVRD). Briefly, this is promoted by programming of immune cell activation (78, 197, 201) eliciting increased insulin resistance, hyperglycemia and hyperlipidemia, and nonalcoholic fatty liver disease (NAFLD). The events allow propagation of further hyperglycemia and hyperlipidemia to allow the progression of NAFLD, liver injury, which involves endoplasmic reticulum stress and reduced autophagy, and worsened type 2 diabetes mellitus (T2DM). The latter metabolic dysfunction combined with the hypertension found in IUGR may promote greater vascular dysfunction and drive exaggerated incidence of CVRD in these offspring. The dashed line indicates that it is important to tease out the contribution of inflammation to both the development of T2DM and NAFLD and the hypothesis that metabolic disease accelerates CVRD in IUGR. This overall response may be even further exaggerated by combined maternal obesity (*) or in the face of adverse diets (**) in these offspring. Dashed lines represent the role for additional integrative mechanisms that mediate IUGR-induced pancreatic and renal dysfunction.