A Comparison of the Gene Expression Profiles of Non-Alcoholic Fatty Liver Disease between Animal Models of a High-Fat Diet and Methionine-Choline-Deficient Diet

Abstract

Non-alcoholic fatty liver disease (NAFLD) embraces several forms of liver disorders involving fat disposition in hepatocytes ranging from simple steatosis to the severe stage, namely, non-alcoholic steatohepatitis (NASH). Recently, several experimental in vivo animal models for NAFLD/NASH have been established. However, no reproducible experimental animal model displays the full spectrum of pathophysiological, histological, molecular, and clinical features associated with human NAFLD/NASH progression. Although methionine-choline-deficient (MCD) diet and high-fat diet (HFD) models can mimic histological and metabolic abnormalities of human disease, respectively, the molecular signaling pathways are extremely important for understanding the pathogenesis of the disease. This review aimed to assess the differences in gene expression patterns and NAFLD/NASH progression pathways among the most common dietary animal models, i.e., HFD- and MCD diet-fed animals. Studies showed that the HFD and MCD diet could induce either up- or downregulation of the expression of genes and proteins that are involved in lipid metabolism, inflammation, oxidative stress, and fibrogenesis pathways. Interestingly, the MCD diet model could spontaneously develop liver fibrosis within two to four weeks and has significant effects on the expression of genes that encode proteins and enzymes involved in the liver fibrogenesis pathway. However, such effects in the HFD model were found to occur after 24 weeks with insulin resistance but appear to cause less severe fibrosis. In conclusion, assessing the abnormal gene expression patterns caused by different diet types provides valuable information regarding the molecular mechanisms of NAFLD/NASH and predicts the clinical progression of the disease. However, expression profiling studies concerning genetic variants involved in the development and progression of NAFLD/NASH should be conducted.

CCN6improves hepatic steatosis, inflammation, and fibrosis in non‐alcoholic steatohepatitis

“…Whilst the ameliorative effect of CCN6 on lipid synthesis gene expression in the HFHC model was not as pronounced as in the MCD model, this may be because of the differences in pathological mechanisms in different murine models that led to minor differences in the expression patterns of some certain genes. As we know, the HFHC model possesses features of MetS that are similar to those of humans, but often fails to fully mimic the histological cellular morphological changes associated with human NASH; whereas the MCD model does not possess the overall manifestation of insulin resistance and metabolic syndrome, and thus fails to well mimic the transition from initial NAFLD steatosis to late NASH in humans 21 . We hypothesize that CCN6 may be more likely to be dominant in mediating fatty acid catabolism.…”

Orthosiphon aristatus (Blume) Miq Alleviates Non-Alcoholic Fatty Liver Disease via Antioxidant Activities in C57BL/6 Obese Mice and Palmitic–Oleic Acid-Induced Steatosis in HepG2 Cells

“…The current results are consistent with previous studies and further support the ability of HFD to induce accumulation of fat in the liver with marked increases in insulin resistance conditions [ 23 ], which in turn increases oxidative stress in the liver causing hepatic lipid peroxidation and triggers inflammatory responses [ 24 ]. Moreover, an insulin resistance condition is usually associated with adipose tissue dysfunction and ectopic lipid deposition [ 2 , 25 ].…”

“…Non-alcoholic fatty liver disease (NAFLD) is the build-up of excess fat in the liver. Early-stage NAFLD does not usually present with symptoms but can progress to serious liver damage, including inflammation, called non-alcoholic steatohepatitis (NASH) and cirrhosis [ 1 , 2 ]. Due to the complex pathophysiology of NAFLD, it has recently been classified as a multi-systemic disease as it is usually associated with cardiovascular disease (CVD), chronic kidney disease, type 2 diabetes, obesity and dyslipidaemia [ 3 ].…”

Immunometabolic factors contributing to obesity-linked hepatocellular carcinoma

“…While addition of cholesterol and fructose to high fat intake seems key to progression of NASH and development of cancer, the mechanisms underlying disease progression are still under investigation ( Ribas et al, 2021 ). In comparison, the methionine and choline deficient diet (MCD) model is a rapid onset and robust dietary model in which liver develops severe steatohepatitis due to defects in lipid droplet and lipoprotein metabolism, but mice fed this diet lack typical associated features of NASH such as obesity and insulin resistance and thus it has limited utility to understand chronic fatty liver stress that leads to NASH ( Haberl et al, 2020 ; Alshawsh et al, 2022 ). Alternatively, the Gubra Amylin NASH inducing diet (40% kcal fat (of these 46% are saturated fatty acids), 22% fructose, 10% sucrose, 2% cholesterol) has a phenotypical and transcriptomic resemblance to clinically presented NASH and emerges upon long term diet exposure ( Hansen et al, 2020 ).…”