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

Abstract

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 non-alcoholic 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 decrease 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 diets 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 (Acly) and fatty-acid synthase (Fasn) 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.

Fatty Acids and Breast Cancer: Make Them on Site or Have Them Delivered

“…ACLY uses citrate to produce acetyl‐CoA and that is subsequently used by FASN as well as for the synthesis of malonyl‐CoA by ACC. Thus, this enzyme links glycolysis with lipogenesis, and expression levels of ACLY have been correlated to the pathology of diseases like non‐alcoholic fatty liver disease (Wang et al, ; Tallino et al, ), type 2 diabetes (Guay et al, ; MacDonald et al, ), obesity, and to many cancers, including that of the breast (Szutowicz et al, ). Likewise, ACC is required for palmitate synthesis due to the use of malonyl‐CoA by FASN, in addition to the important regulatory functions of malonyl‐CoA in the cell, as previously mentioned.…”

Host Cell Copper Transporters CTR1 and ATP7A are important for Influenza A virus replication

“…Copper metabolism is important in a number of host functions, with diet and therapeutics under investigation for several genetic and developmental defects in rodent models [14, 51]. Here we show that cellular copper homeostasis is linked to the influenza A virus life cycle.…”

“…Copper is an important cofactor for a number of critical cellular processes, including cellular respiration and mitigation of oxidative stress. Many additional copper-dependent processes are observed in specific tissues, such as modulation of lipid metabolism in the liver [13, 14], and neurotransmitter processing in the brain [15, 16]. In the lung and respiratory tract, extracellular matrix synthesis requires the copper-containing enzyme lysyl oxidase [17].…”

The role of insufficient copper in lipid synthesis and fatty‐liver disease

“…This study also analyzed a rat model of NAFLD and revealed a histopathological response consistent with NAFLD in rats fed a CuD diet, supporting the link between CuD and hepatic dyslipidemia. Several other groups have reported NAFLD‐like symptoms in animal models fed diets deficient in copper, including transcriptomics analysis that found increased expression of transcripts associated with inflammation, fibrosis, and hepatic stellate cell activation, all consistent with NAFLD progression . More recently, a second clinical study confirmed the inverse correlation between hepatic copper content and the extent of steatosis , but also revealed the important finding that the correlation only held in patients without MetS.…”

“…Marginal CuD has recently gained attention in a number of diseases including Alzheimer's disease, ischemic heart disease (IHD), non‐alcoholic fatty‐liver disease (NAFLD), and obesity . Many of these clinical manifestations have been linked with alterations in lipid metabolism and ultimately dyslipidemia , including abnormal cholesterol metabolism in Alzheimer's disease (recently reviewed here: ref.…”