The Association Between Hepatic Steatosis and Glucose Metabolic Dysfunction

Abstract

Non-alcoholic fatty liver disease (NAFLD) is a growing global concern especially in Western countries, primarily resulting from poor nutritional habits. This disorder can manifest as early as the neonatal period suggesting that even in that period nutrition may play a role. While previous reports demonstrated that formulas rich in medium-chain fatty acids (MCFAs) play a significant role in the NAFLD development in a neonatal pig model by comparison to long-chain fatty acid (LCFA). However, how the energy content of these formulas influences NAFLD pathogenesis remains unclear. Our hypothesis was that MCFAs induce NAFLD in neonatal pigs independent of energy content, and that MCFA-induced NAFLD disrupts hepatic glucose metabolism through dysregulation of key glucose metabolic and insulin signaling pathways. Pigs (n = 6) were fed either MCFA or LCFA at high or low inclusion levels for 20 d in a 2 × 2 factorial design. Fractional body weight increased throughout the experimental period and was greater for pigs fed the LCFA compared with those fed the MCFA formulas on day 21 (P < 0.01). Although pigs fed LCFA formulas maintained similar body weights regardless of energy content, those on high-energy formulas had less lean and greater fat mass (P < 0.05). The same pattern occurred in MCFA-fed pigs, where similar body weights masked a shift from lean to fat mass in the high-energy group (P < 0.05). Hepatic fat percentage was greater in MCFA-fed than LCFA-fed pigs (P < 0.0001) and greater in high-energy versus low-energy groups (P < 0.0001). The key lipogenic transcription factors involved in regulating lipogenic and lipolytic pathways were upregulated in response to greater energy content regardless of fat type, along with their downstream target genes (P < 0.05). However, DNL index was greater for pigs fed the MCFA compared with those fed LCFA (P < 0.0001). The relative mRNA expression of glycolytic, and gluconeogenic genes was upregulated in high energy fed pigs (P < 0.05), without any significant differences in blood glucose and insulin concentrations. Our data suggest that while excess energy contributes to hepatic steatosis, MCFAs are a primary driver of this condition independent of caloric content, with consequential effects on hepatic glucose metabolism.