Hyperglycemia-stimulating diet induces liver steatosis in sheep

Sci Rep. 2020 Jul 22;10(1):12189. doi: 10.1038/s41598-020-68909-z.

Abstract

Hepatic steatosis is strongly associated with chronic liver disease and systemic metabolic disorder. Adipose lipolysis is a recognized principal source of intrahepatic fat in various metabolic disorders, including non-alcoholic fatty liver disease. We hypothesized that, in the premorbid state, hepatic de novo lipogenesis (DNL) driven by excess carbohydrates abundance might play a more significant role. We employed a novel nutritional model in sheep of two distinct carbohydrates abundances. During 4 months of the dietary treatment, lambs were monitored for metabolic and terminal liver parameters. Lambs grown on the high-calorie (HC) diet were consistently more hyperglycemic and hyperinsulinemic than lambs grown on the lower-calorie (LC) diet (P < 0.0001). As a result, the HC lambs developed systemic- (HOMA-IR of 7.3 vs. 3.1; P < 0.0001), and adipose- (ADIPO-IR of 342.7 vs. 74.4; P < 0.0001) insulin resistance, significant adiposity (P < 0.0001), and higher plasma triglycerides (P < 0.05). Circulating leukocytes in the HC lambs had higher mRNA expression levels of the proinflammatory markers CCL2 (P < 0.01) and TNF-alpha (P < 0.04), and IL1B trended higher (P < 0.1). Remarkably, lambs on the HC diet developed substantial liver steatosis (mean fat content of 8.1 vs. 5.3% in the LC group; P < 0.0001) with a higher histological steatosis score (2.1 vs. 0.4; P < 0.0002). Hepatic steatosis was most-strongly associated with blood glucose and insulin levels but negatively correlated with circulating fatty acids-indicating a more significant contribution from hepatic DNL than from adipose lipolysis. Sheep may prove an attractive large-animal model of fatty liver and metabolic comorbidities resulting from excess carbohydrate-based energy early in life.

MeSH terms

  • Adipose Tissue / metabolism
  • Animals
  • Blood Glucose / analysis
  • Chemokine CCL2 / genetics
  • Chemokine CCL2 / metabolism
  • Diet* / veterinary
  • Fatty Acids, Nonesterified / metabolism
  • Hyperglycemia / complications
  • Hyperglycemia / pathology*
  • Interleukin-1beta / genetics
  • Interleukin-1beta / metabolism
  • Leukocytes / cytology
  • Leukocytes / metabolism
  • Lipolysis
  • Liver / metabolism
  • Liver / pathology
  • Male
  • Non-alcoholic Fatty Liver Disease / etiology
  • Non-alcoholic Fatty Liver Disease / pathology*
  • Severity of Illness Index
  • Sheep
  • Triglycerides / blood
  • Tumor Necrosis Factor-alpha / genetics
  • Tumor Necrosis Factor-alpha / metabolism

Substances

  • Blood Glucose
  • Chemokine CCL2
  • Fatty Acids, Nonesterified
  • Interleukin-1beta
  • Triglycerides
  • Tumor Necrosis Factor-alpha