Genetic Polymorphisms and Diversity in Nonalcoholic Fatty Liver Disease (NAFLD): A Mini Review

Sulaiman, Siti Aishah; Dorairaj, Vicneswarry; Adrus, Muhammad Nafiz Haidi

doi:10.3390/biomedicines11010106

Cited by 14 publications

(9 citation statements)

References 207 publications

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“…As mentioned above, several genetic polymorphisms are associated with NAFLD risk [158]. As a means of investigating the effect of the PNPLA3 I148M mutation, Kostrzewski et al cultured human hepatocytes, KCs, and mutated HSCs in perfused LOC platforms [159].…”

Section: Liver-on-a-chipmentioning

confidence: 99%

NAFLD-Related HCC: Focus on the Latest Relevant Preclinical Models

Fang

Celton-Morizur

2023

Cancers

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Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer and one of the deadliest cancers worldwide. Despite extensive research, the biological mechanisms underlying HCC’s development and progression remain only partially understood. Chronic overeating and/or sedentary-lifestyle-associated obesity, which promote Non-Alcoholic Fatty Liver Disease (NAFLD), have recently emerged as worrying risk factors for HCC. NAFLD is characterized by excessive hepatocellular lipid accumulation (steatosis) and affects one quarter of the world’s population. Steatosis progresses in the more severe inflammatory form, Non-Alcoholic Steatohepatitis (NASH), potentially leading to HCC. The incidence of NASH is expected to increase by up to 56% over the next 10 years. Better diagnoses and the establishment of effective treatments for NAFLD and HCC will require improvements in our understanding of the fundamental mechanisms of the disease’s development. This review describes the pathogenesis of NAFLD and the mechanisms underlying the transition from NAFL/NASH to HCC. We also discuss a selection of appropriate preclinical models of NAFLD for research, from cellular models such as liver-on-a-chip models to in vivo models, focusing particularly on mouse models of dietary NAFLD-HCC.

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Section: Liver-on-a-chipmentioning

confidence: 99%

NAFLD-Related HCC: Focus on the Latest Relevant Preclinical Models

Fang

Celton-Morizur

2023

Cancers

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“… 30 Monosaccharides enter the liver, and fructose is metabolized into fructose-1-P and further into acetyl-CoA, fueling DNL. 12 Fructose, glucose, and insulin activate ChREBP & SREBP-1c, which transcriptionally activates genes in DNL. FA accumulation can exceed the liver’s capacity, which leads to ectopic lipid deposition and lipotoxicity.…”

Section: The Role Of Sugar In Nafld Pathophysiologymentioning

confidence: 99%

“…These differences are largely due to socioeconomic factors, sugar consumption, and, in part, due to the population prevalence of genetic polymorphisms underlying the susceptibility for developing NAFLD. 12 , 13 In the United States, the highest prevalence of NAFLD is seen in those of Hispanic heritage, possibly driven by the inheritance of the most prevalent polymorphism associated with NAFLD, patatin-like phospholipase domain–containing protein three (PNPLA3). 14 …”

Section: Introductionmentioning

confidence: 99%

The Impact and Burden of Dietary Sugars on the Liver

Huneault,

Ramirez Tovar,

Sanchez-Torres

et al. 2023

Hepatology Communications

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NAFLD, or metabolic dysfunction–associated steatotic liver disease, has increased in prevalence hand in hand with the rise in obesity and increased free sugars in the food supply. The causes of NAFLD are genetic in origin combined with environmental drivers of the disease phenotype. Dietary intake of added sugars has been shown to have a major role in the phenotypic onset and progression of the disease. Simple sugars are key drivers of steatosis, likely through fueling de novo lipogenesis, the conversion of excess carbohydrates into fatty acids, but also appear to upregulate lipogenic metabolism and trigger hyperinsulinemia, another driver. NAFLD carries a clinical burden as it is associated with obesity, type 2 diabetes, metabolic syndrome, and cardiovascular disease. Patient quality of life is also impacted, and there is an enormous economic burden due to healthcare use, which is likely to increase in the coming years. This review aims to discuss the role of dietary sugar in NAFLD pathogenesis, the health and economic burden, and the promising potential of sugar reduction to improve health outcomes for patients with this chronic liver disease.

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“…Patients with MASH are at a higher risk of liver cancer, liver failure, and cardiovascular disease than are healthy individuals [ 2 , 5 ]. Key risk factors for MASH include diabetes, obesity, age, ethnicity, sex, and genetic polymorphisms, which can also affect MASH progression [ 7 , 8 ]. These risk factors reflect the complex and heterogeneous nature of MASH [ 9 ].…”

Section: Introductionmentioning

confidence: 99%

Phenotypic and metabolomic characteristics of mouse models of metabolic associated steatohepatitis

Yang,

Lin,

Shen

et al. 2024

Biomark Res

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Background Metabolic associated steatohepatitis (MASH) is metabolic disease that may progress to cirrhosis and hepatocellular carcinoma. Mouse models of diet-induced MASH, which is characterized by the high levels of fats, sugars, and cholesterol in diets, are commonly used in research. However, mouse models accurately reflecting the progression of MASH in humans remain to be established. Studies have explored the potential use of serological metabolites as biomarkers of MASH severity in relation to human MASH. Methods We performed a comparative analysis of three mouse models of diet-induced MASH in terms of phenotypic and metabolomic characteristics; MASH was induced using different diets: a high-fat diet; a Western diet; and a high-fat, high-cholesterol diet. Liver cirrhosis was diagnosed using standard clinical approaches (e.g., METAVIR score, hyaluronan level, and collagen deposition level). Mouse serum samples were subjected to nuclear magnetic resonance spectroscopy–based metabolomic profiling followed by bioinformatic analyses. Metabolomic analysis of a retrospective cohort of patients with hepatocellular carcinoma was performed; the corresponding cirrhosis scores were also evaluated. Results Using clinically relevant quantitative diagnostic methods, the severity of MASH was evaluated. Regarding metabolomics, the number of lipoprotein metabolites increased with both diet and MASH progression. Notably, the levels of very low-density lipoprotein (VLDL) and low-density lipoprotein (LDL) significantly increased with fibrosis progression. During the development of diet-induced MASH in mice, the strongest upregulation of expression was noted for VLDL receptor. Metabolomic analysis of a retrospective cohort of patients with cirrhosis indicated lipoproteins (e.g., VLDL and LDL) as predominant biomarkers of cirrhosis. Conclusions Our findings provide insight into the pathophysiology and metabolomics of experimental MASH and its relevance to human MASH. The observed upregulation of lipoprotein expression reveals a feedforward mechanism for MASH development that may be targeted for the development of noninvasive diagnosis.

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Genetic Polymorphisms and Diversity in Nonalcoholic Fatty Liver Disease (NAFLD): A Mini Review

Cited by 14 publications

References 207 publications

NAFLD-Related HCC: Focus on the Latest Relevant Preclinical Models

NAFLD-Related HCC: Focus on the Latest Relevant Preclinical Models

The Impact and Burden of Dietary Sugars on the Liver

Phenotypic and metabolomic characteristics of mouse models of metabolic associated steatohepatitis

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