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MicroRNA Expression Relating to Dietary-Induced Liver Steatosis and NASH.

Zarfeshani A, Ngo S, Sheppard AM - J Clin Med (2015)

Bottom Line: Health issues associated with excessive caloric intake and sedentary lifestyle are driving a modern "epidemic" of liver disease.Often developing as a sequela of obesity, non-alcoholic fatty liver disease (NAFLD) arises in almost one-third of people initially carrying excess hepatic fat and is likely the result of the liver's limited capacity to cope with the modern-day levels of dietary fatty acids circulating in the blood.A general reluctance to undergo such screening means that the prevalence of NASH is likely to be under reported and, thus, risk assessment for future metabolic syndrome (MetS) markedly compromised.

View Article: PubMed Central - PubMed

Affiliation: Developmental Epigenetics Group, Liggins Institute, The University of Auckland, 85 Park Road, Grafton, Auckland 1023, New Zealand. a.zarfeshani@auckland.ac.nz.

ABSTRACT
Health issues associated with excessive caloric intake and sedentary lifestyle are driving a modern "epidemic" of liver disease. Initially presenting in the clinic as an excessive accumulation of fat within hepatocyte cells (steatosis), the progression to more severe non-alcoholic steatohepatitis (NASH) in which liver damage and inflammation are overt features, is becoming increasingly common. Often developing as a sequela of obesity, non-alcoholic fatty liver disease (NAFLD) arises in almost one-third of people initially carrying excess hepatic fat and is likely the result of the liver's limited capacity to cope with the modern-day levels of dietary fatty acids circulating in the blood. While routine imaging can readily assess the presence and level of "extra-hepatic fat", a proper diagnosis of disease progression to NASH is currently only possible by liver biopsy. A general reluctance to undergo such screening means that the prevalence of NASH is likely to be under reported and, thus, risk assessment for future metabolic syndrome (MetS) markedly compromised. The seemingly inevitable progression to overt insulin resistance that characterizes MetS may in part be the consequence of the body's attempt to cope with NAFLD by driving systemic insulin sensitivity and, thus, fatty acid breakdown. The potential significance of miRNAs in both physiological homeostasis and pathogenesis is increasingly appreciated and in the liver may contribute specifically to the regulation of lipid pathways and NAFLD progression. As such, they may have utility as molecular indicators for the accurate profiling of both initial risk and disease progression from simple steatosis to NASH, and further to fibrosis/cirrhosis.

No MeSH data available.


Related in: MedlinePlus

Hepatic triglyceride (TG) accumulation. FFAs are derived from the diet or synthesized de novo by hepatocytes. High levels of dietary protein intake (leading to increased circulating BCAA) can induce peripheral IR by inhibiting insulin signaling, resulting in increased uptake of glucose and TG storage in hepatocytes. Meanwhile, IR in adipose tissue reduces the inhibitory effect of insulin on lipoprotein lipase, resulting in increased lipolysis (i.e., breakdown of TG) and, thus, to increased circulating FAs to be taken up by the liver. Hyperinsulinemia can also induce de novo synthesis of FFAs in hepatocytes, leading to hepatic TG synthesis. These pathways drive hepatic TG accumulation and ultimately may contribute to the development of NASH. IR: insulin resistance; FFA: free fatty acid; BCAA: branched-chain amino acid; NASH: non-alcoholic steatohepatitis; VLDL: very low-density lipoprotein.
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jcm-04-01938-f001: Hepatic triglyceride (TG) accumulation. FFAs are derived from the diet or synthesized de novo by hepatocytes. High levels of dietary protein intake (leading to increased circulating BCAA) can induce peripheral IR by inhibiting insulin signaling, resulting in increased uptake of glucose and TG storage in hepatocytes. Meanwhile, IR in adipose tissue reduces the inhibitory effect of insulin on lipoprotein lipase, resulting in increased lipolysis (i.e., breakdown of TG) and, thus, to increased circulating FAs to be taken up by the liver. Hyperinsulinemia can also induce de novo synthesis of FFAs in hepatocytes, leading to hepatic TG synthesis. These pathways drive hepatic TG accumulation and ultimately may contribute to the development of NASH. IR: insulin resistance; FFA: free fatty acid; BCAA: branched-chain amino acid; NASH: non-alcoholic steatohepatitis; VLDL: very low-density lipoprotein.

Mentions: A combination of dietary-based caloric excess and a sedentary lifestyle (confounded by socioeconomic factors) has led to population-wide weight gain and, subsequently, an increasing incidence of obesity-related comorbidities (e.g., non-alcoholic fatty liver (NAFLD), type 2 diabetes mellitus (T2DM) and cardiovascular diseases) [1,2]. In addition to driving the uptake and “storage” of excess circulating fatty acids (FAs) into peripheral tissues, this generalized metabolic syndrome (MetS) is also characterized by elevated triglyceride (TG) synthesis, leading to yet further fat accumulation, particularly in liver and adipose tissues [3] (Figure 1). The abnormal accumulation of fat in the liver (occurring in the absence of significant alcohol consumption) is a defining characteristic of NAFLD and begins with the intra-cytoplasmic accumulation of TG as liposomes around the hepatocyte nucleus. At more advanced stages, these vesicles increase in size, such that the nucleus is distorted and displaced to the periphery of the hepatocyte, a condition that is known as macrovesicular steatosis [4]. The pathological spectrum of NAFLD progresses then to non-alcoholic steatohepatitis (NASH), which is defined by the additional degeneration of the hepatocytes and sinusoidal fibrosis [4,5] and, finally, to end-stage cirrhosis, the main driver of liver transplant interventions [6,7].


MicroRNA Expression Relating to Dietary-Induced Liver Steatosis and NASH.

Zarfeshani A, Ngo S, Sheppard AM - J Clin Med (2015)

Hepatic triglyceride (TG) accumulation. FFAs are derived from the diet or synthesized de novo by hepatocytes. High levels of dietary protein intake (leading to increased circulating BCAA) can induce peripheral IR by inhibiting insulin signaling, resulting in increased uptake of glucose and TG storage in hepatocytes. Meanwhile, IR in adipose tissue reduces the inhibitory effect of insulin on lipoprotein lipase, resulting in increased lipolysis (i.e., breakdown of TG) and, thus, to increased circulating FAs to be taken up by the liver. Hyperinsulinemia can also induce de novo synthesis of FFAs in hepatocytes, leading to hepatic TG synthesis. These pathways drive hepatic TG accumulation and ultimately may contribute to the development of NASH. IR: insulin resistance; FFA: free fatty acid; BCAA: branched-chain amino acid; NASH: non-alcoholic steatohepatitis; VLDL: very low-density lipoprotein.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4663477&req=5

jcm-04-01938-f001: Hepatic triglyceride (TG) accumulation. FFAs are derived from the diet or synthesized de novo by hepatocytes. High levels of dietary protein intake (leading to increased circulating BCAA) can induce peripheral IR by inhibiting insulin signaling, resulting in increased uptake of glucose and TG storage in hepatocytes. Meanwhile, IR in adipose tissue reduces the inhibitory effect of insulin on lipoprotein lipase, resulting in increased lipolysis (i.e., breakdown of TG) and, thus, to increased circulating FAs to be taken up by the liver. Hyperinsulinemia can also induce de novo synthesis of FFAs in hepatocytes, leading to hepatic TG synthesis. These pathways drive hepatic TG accumulation and ultimately may contribute to the development of NASH. IR: insulin resistance; FFA: free fatty acid; BCAA: branched-chain amino acid; NASH: non-alcoholic steatohepatitis; VLDL: very low-density lipoprotein.
Mentions: A combination of dietary-based caloric excess and a sedentary lifestyle (confounded by socioeconomic factors) has led to population-wide weight gain and, subsequently, an increasing incidence of obesity-related comorbidities (e.g., non-alcoholic fatty liver (NAFLD), type 2 diabetes mellitus (T2DM) and cardiovascular diseases) [1,2]. In addition to driving the uptake and “storage” of excess circulating fatty acids (FAs) into peripheral tissues, this generalized metabolic syndrome (MetS) is also characterized by elevated triglyceride (TG) synthesis, leading to yet further fat accumulation, particularly in liver and adipose tissues [3] (Figure 1). The abnormal accumulation of fat in the liver (occurring in the absence of significant alcohol consumption) is a defining characteristic of NAFLD and begins with the intra-cytoplasmic accumulation of TG as liposomes around the hepatocyte nucleus. At more advanced stages, these vesicles increase in size, such that the nucleus is distorted and displaced to the periphery of the hepatocyte, a condition that is known as macrovesicular steatosis [4]. The pathological spectrum of NAFLD progresses then to non-alcoholic steatohepatitis (NASH), which is defined by the additional degeneration of the hepatocytes and sinusoidal fibrosis [4,5] and, finally, to end-stage cirrhosis, the main driver of liver transplant interventions [6,7].

Bottom Line: Health issues associated with excessive caloric intake and sedentary lifestyle are driving a modern "epidemic" of liver disease.Often developing as a sequela of obesity, non-alcoholic fatty liver disease (NAFLD) arises in almost one-third of people initially carrying excess hepatic fat and is likely the result of the liver's limited capacity to cope with the modern-day levels of dietary fatty acids circulating in the blood.A general reluctance to undergo such screening means that the prevalence of NASH is likely to be under reported and, thus, risk assessment for future metabolic syndrome (MetS) markedly compromised.

View Article: PubMed Central - PubMed

Affiliation: Developmental Epigenetics Group, Liggins Institute, The University of Auckland, 85 Park Road, Grafton, Auckland 1023, New Zealand. a.zarfeshani@auckland.ac.nz.

ABSTRACT
Health issues associated with excessive caloric intake and sedentary lifestyle are driving a modern "epidemic" of liver disease. Initially presenting in the clinic as an excessive accumulation of fat within hepatocyte cells (steatosis), the progression to more severe non-alcoholic steatohepatitis (NASH) in which liver damage and inflammation are overt features, is becoming increasingly common. Often developing as a sequela of obesity, non-alcoholic fatty liver disease (NAFLD) arises in almost one-third of people initially carrying excess hepatic fat and is likely the result of the liver's limited capacity to cope with the modern-day levels of dietary fatty acids circulating in the blood. While routine imaging can readily assess the presence and level of "extra-hepatic fat", a proper diagnosis of disease progression to NASH is currently only possible by liver biopsy. A general reluctance to undergo such screening means that the prevalence of NASH is likely to be under reported and, thus, risk assessment for future metabolic syndrome (MetS) markedly compromised. The seemingly inevitable progression to overt insulin resistance that characterizes MetS may in part be the consequence of the body's attempt to cope with NAFLD by driving systemic insulin sensitivity and, thus, fatty acid breakdown. The potential significance of miRNAs in both physiological homeostasis and pathogenesis is increasingly appreciated and in the liver may contribute specifically to the regulation of lipid pathways and NAFLD progression. As such, they may have utility as molecular indicators for the accurate profiling of both initial risk and disease progression from simple steatosis to NASH, and further to fibrosis/cirrhosis.

No MeSH data available.


Related in: MedlinePlus