Abstract:The fatty acid transport protein 5 (FATP5) is exclusively expressed in the liver and is involved in hepatic lipid and bile metabolism. We investigated whether a variation in the FATP5 promoter (rs56225452) is associated with hepatic steatosis and further features of the metabolic syndrome. A total of 716 male subjects from the Metabolic Intervention Cohort Kiel (MICK) and 103 male subjects with histologically proved nonalcoholic fatty liver disease (NAFLD) were genotyped for this FATP5 polymorphism rs56225452 … Show more
“…In contrast, a small study found no difference in hepatic FATP5 gene expression between individuals with ( n = 16) and without ( n = 8) hepatic steatosis [19]. FATP5 promotor polymorphism (rs56225452), representing a putative gain-of-function mutation in the FATP5 promotor, correlated with BMI-dependent hepatic steatosis in males with biopsy proven NAFLD ( n = 103) [20], suggesting that genetic variation may underlie part of the contribution of FATP5 in NAFLD. However, additional studies are required to extend our present understanding of the role of FATP in clinical NAFLD.Fig.…”
Non-alcoholic fatty liver disease (NAFLD) is currently the world’s most common liver disease, estimated to affect up to one-fourth of the population. Hallmarked by hepatic steatosis, NAFLD is associated with a multitude of detrimental effects and increased mortality. This narrative review investigates the molecular mechanisms of hepatic steatosis in NAFLD, focusing on the four major pathways contributing to lipid homeostasis in the liver. Hepatic steatosis is a consequence of lipid acquisition exceeding lipid disposal, i.e., the uptake of fatty acids and de novo lipogenesis surpassing fatty acid oxidation and export. In NAFLD, hepatic uptake and de novo lipogenesis are increased, while a compensatory enhancement of fatty acid oxidation is insufficient in normalizing lipid levels and may even promote cellular damage and disease progression by inducing oxidative stress, especially with compromised mitochondrial function and increased oxidation in peroxisomes and cytochromes. While lipid export initially increases, it plateaus and may even decrease with disease progression, sustaining the accumulation of lipids. Fueled by lipo-apoptosis, hepatic steatosis leads to systemic metabolic disarray that adversely affects multiple organs, placing abnormal lipid metabolism associated with NAFLD in close relation to many of the current life-style-related diseases.
“…In contrast, a small study found no difference in hepatic FATP5 gene expression between individuals with ( n = 16) and without ( n = 8) hepatic steatosis [19]. FATP5 promotor polymorphism (rs56225452), representing a putative gain-of-function mutation in the FATP5 promotor, correlated with BMI-dependent hepatic steatosis in males with biopsy proven NAFLD ( n = 103) [20], suggesting that genetic variation may underlie part of the contribution of FATP5 in NAFLD. However, additional studies are required to extend our present understanding of the role of FATP in clinical NAFLD.Fig.…”
Non-alcoholic fatty liver disease (NAFLD) is currently the world’s most common liver disease, estimated to affect up to one-fourth of the population. Hallmarked by hepatic steatosis, NAFLD is associated with a multitude of detrimental effects and increased mortality. This narrative review investigates the molecular mechanisms of hepatic steatosis in NAFLD, focusing on the four major pathways contributing to lipid homeostasis in the liver. Hepatic steatosis is a consequence of lipid acquisition exceeding lipid disposal, i.e., the uptake of fatty acids and de novo lipogenesis surpassing fatty acid oxidation and export. In NAFLD, hepatic uptake and de novo lipogenesis are increased, while a compensatory enhancement of fatty acid oxidation is insufficient in normalizing lipid levels and may even promote cellular damage and disease progression by inducing oxidative stress, especially with compromised mitochondrial function and increased oxidation in peroxisomes and cytochromes. While lipid export initially increases, it plateaus and may even decrease with disease progression, sustaining the accumulation of lipids. Fueled by lipo-apoptosis, hepatic steatosis leads to systemic metabolic disarray that adversely affects multiple organs, placing abnormal lipid metabolism associated with NAFLD in close relation to many of the current life-style-related diseases.
“…Patients with conditions resulting from mutations in LpL (for example, hyperlipoproteinaemia type 1) are prone to developing insulin resistance 41 . In humans, the single nucleotide polymorphism (SNP) rs56225452, putatively representing a gain-of-function mutation in the FATP5 promoter, was associated with insulin resistance and NAFLD 42 . In Asian Indian individuals, as well as those of other ethnic groups, variants (C-482T, T-455C or both) in apolipoprotein C3 (APOC3), which can inhibit LpL and hepatic lipase, are associated with hypertriglyceridaemia and NAFLD 43 .…”
Section: Regulation Of Fat Delivery To Livermentioning
Non-alcoholic fatty liver disease and its downstream sequelae, hepatic insulin resistance and type 2 diabetes, are rapidly growing epidemics, which lead to increased morbidity and mortality rates, and soaring health-care costs. Developing interventions requires a comprehensive understanding of the mechanisms by which excess hepatic lipid develops and causes hepatic insulin resistance and type 2 diabetes. Proposed mechanisms implicate various lipid species, inflammatory signalling and other cellular modifications. Studies in mice and humans have elucidated a key role for hepatic diacylglycerol activation of protein kinase Cε in triggering hepatic insulin resistance. Therapeutic approaches based on this mechanism could alleviate the related epidemics of non-alcoholic fatty liver disease and type 2 diabetes.
“…A group of 716 male subjects was analyzed for a potential relationship among a FATP5 polymorphism and liver disease susceptibility [60]. A G-to-A substitution, detected in the gene promoter and the rare A-allele was shown to associate with a cluster of worsened metabolic parameters: higher post-prandial TAG and insulin, lowered insulin sensitivity index and elevated ALT.…”
Section: Polymorphisms and Mutations In Human Fatp Genesmentioning
Uptake of long-chain fatty acids plays pivotal roles in metabolic homeostasis and human physiology. Uptake rates must be controlled in an organ-specific fashion to balance storage with metabolic needs during transitions between fasted and fed states. Many obesity-associated diseases, such as insulin resistance in skeletal muscle, cardiac lipotoxicity, and hepatic steatosis, are thought to be driven by the overflow of fatty acids from adipose stores and the subsequent ectopic accumulation of lipids resulting in apoptosis, ER stress, and inactivation of the insulin receptor signaling cascade. Thus, it is of critical importance to understand the components that regulate the flux of fatty acid between the different organ systems. Cellular uptake of fatty acids by key metabolic organs, including the intestine, adipose tissue, muscle, heart, and liver, has been shown to be protein mediated and various unique combinations of fatty acid transport proteins (FATPs/SLC27A1-6) are expressed by all of these tissues. Here we review our current understanding of how FATPs can contribute to normal physiology and how FATP mutations as well as hypo- and hypermorphic changes contribute to disorders ranging from cardiac lipotoxicity to hepatosteatosis and ichthyosis. Ultimately, our increasing knowledge of FATP biology has the potential to lead to the development of new diagnostic tools and treatment options for some of the most pervasive chronic human disorders.
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