TY - JOUR
T1 - Nutrigenomics analysis reveals that copper deficiency and dietary sucrose up-regulate inflammation, fibrosis and lipogenic pathways in a mature rat model of nonalcoholic fatty liver disease
AU - Tallino, Savannah
AU - Duffy, Megan
AU - Ralle, Martina
AU - Cortés, María Paz
AU - Latorre, Mauricio
AU - Burkhead, Jason L.
N1 - Publisher Copyright:
© 2015 The Authors.
PY - 2015/10/1
Y1 - 2015/10/1
N2 - Nonalcoholic fatty liver disease (NAFLD) prevalence is increasing worldwide, with the affected US population estimated near 30%. Diet is a recognized risk factor in the NAFLD spectrum, which includes nonalcoholic steatohepatitis (NASH) and fibrosis. Low hepatic copper (Cu) was recently linked to clinical NAFLD/NASH severity. Simple sugar consumption including sucrose and fructose is implicated in NAFLD, while consumption of these macronutrients also decreases liver Cu levels. Though dietary sugar and low Cu are implicated in NAFLD, transcript-level responses that connect diet and pathology are not established. We have developed a mature rat model of NAFLD induced by dietary Cu deficiency, human-relevant high sucrose intake (30% w/w) or both factors in combination. Compared to the control diet with adequate Cu and 10% (w/w) sucrose, rats fed either high-sucrose or low-Cu diet had increased hepatic expression of genes involved in inflammation and fibrogenesis, including hepatic stellate cell activation, while the combination of diet factors also increased ATP citrate lyase and fatty acid synthase gene transcription (fold change >2, P<0.02). Low dietary Cu decreased hepatic and serum Cu (. P≤0.05), promoted lipid peroxidation and induced NAFLD-like histopathology, while the combined factors also induced fasting hepatic insulin resistance and liver damage. Neither low Cu nor 30% sucrose in the diet led to enhanced weight gain. Taken together, transcript profiles, histological and biochemical data indicate that low Cu and high sucrose promote hepatic gene expression and physiological responses associated with NAFLD and NASH, even in the absence of obesity or severe steatosis.
AB - Nonalcoholic fatty liver disease (NAFLD) prevalence is increasing worldwide, with the affected US population estimated near 30%. Diet is a recognized risk factor in the NAFLD spectrum, which includes nonalcoholic steatohepatitis (NASH) and fibrosis. Low hepatic copper (Cu) was recently linked to clinical NAFLD/NASH severity. Simple sugar consumption including sucrose and fructose is implicated in NAFLD, while consumption of these macronutrients also decreases liver Cu levels. Though dietary sugar and low Cu are implicated in NAFLD, transcript-level responses that connect diet and pathology are not established. We have developed a mature rat model of NAFLD induced by dietary Cu deficiency, human-relevant high sucrose intake (30% w/w) or both factors in combination. Compared to the control diet with adequate Cu and 10% (w/w) sucrose, rats fed either high-sucrose or low-Cu diet had increased hepatic expression of genes involved in inflammation and fibrogenesis, including hepatic stellate cell activation, while the combination of diet factors also increased ATP citrate lyase and fatty acid synthase gene transcription (fold change >2, P<0.02). Low dietary Cu decreased hepatic and serum Cu (. P≤0.05), promoted lipid peroxidation and induced NAFLD-like histopathology, while the combined factors also induced fasting hepatic insulin resistance and liver damage. Neither low Cu nor 30% sucrose in the diet led to enhanced weight gain. Taken together, transcript profiles, histological and biochemical data indicate that low Cu and high sucrose promote hepatic gene expression and physiological responses associated with NAFLD and NASH, even in the absence of obesity or severe steatosis.
KW - Copper
KW - Fibrosis
KW - Inflammation
KW - Liver
KW - Nonalcoholic steatohepatitis
KW - Steatosis
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U2 - 10.1016/j.jnutbio.2015.04.009
DO - 10.1016/j.jnutbio.2015.04.009
M3 - Article
C2 - 26033743
AN - SCOPUS:84942551023
SN - 0955-2863
VL - 26
SP - 996
EP - 1006
JO - Journal of Nutritional Biochemistry
JF - Journal of Nutritional Biochemistry
IS - 10
ER -