Unique genetic features of lean NAFLD: A review of mechanisms and clinical implications
image: (A) Due to PNPLA3 defects. Genetic defects in PNPLA3 result in decreased hydrolysis of triglycerides to fatty acids. This leads to increased intrahepatic triglycerides and decreased exportation of VLDL generating hepatic steatosis. (B) Due to TM6SF2 defects. Genetic defects in TM6SF2 decrease the hepatic export of VLDL. This increases intrahepatic triglycerides causing hepatic steatosis. (C) Due to ApoB defects. Genetic defects in ApoB result in decreased packaging of fatty acids in the ER leading to increased intrahepatic triglycerides and decreased hepatic export of VLDL giving rise to hepatic steatosis. (D) Due to LAL defects. Genetic defects in LAL result in decreased lysosomal breakdown of LDL into free cholesterol and fatty acids. This leads to increased intrahepatic LDL, upregulation of LDL receptors, and stimulation of HMGCoA-R with subsequent increased cholesterol production. ABCA1, ATP-binding cassette A1; ACAT, acetyl-coenzyme A acetyltransferase; ApoB, apolipoprotein B; DNL, de novo lipogenesis; ER, endoplasmic reticulum; FFAs, free fatty acids; GCKR, glucokinase regulator; HDL, high-density lipoprotein; HMGCoA-R, 3-hydroxy-3-methylglutaryl-CoA reductase; LAL, lysosomal acid lipase; LDL, low-density lipoprotein; LDL-R, low-density lipoprotein receptor; LXRs, liver X receptors; SREBPs, steroid regulation binding proteins; PNPLA3, palatine-like phospholipase domain-containing-3; TG, triglyceride; TM6SF2, transmembrane 6 superfamily member 2; VLDL, very low-density lipoprotein.
Credit: Jasmine Tidwell, George Y. Wu
Non-alcoholic fatty liver disease (NAFLD) affects 25% of the global population. About 20% of these individuals have a normal body mass index (BMI), known as lean NAFLD. Unlike typical NAFLD cases associated with obesity and diabetes, lean NAFLD results from mechanisms not related to excess weight or insulin resistance. Genetic factors are major contributors to lean NAFLD, and genome-wide association studies have identified several associated genes. This review aims to increase awareness by describing the genetic markers linked to NAFLD and the defects involved in the development of lean NAFLD.
Unlike typical NAFLD associated with obesity and diabetes, lean NAFLD affects individuals with a normal BMI, accounting for about 20% of NAFLD cases. This variant is not linked to excess weight or insulin resistance, indicating alternative underlying mechanisms. Understanding these mechanisms is crucial for developing effective diagnostic and therapeutic strategies for lean NAFLD.
Lean NAFLD poses unique diagnostic and therapeutic challenges due to its atypical presentation. The absence of obesity often leads to delayed diagnosis and management, as the condition is not immediately suspected in lean individuals. As a result, patients with lean NAFLD may experience more advanced liver disease by the time of diagnosis. Increasing awareness and understanding of lean NAFLD is essential for early detection and intervention.
Recent genome-wide association studies (GWAS) have identified several genetic variants associated with lean NAFLD. Key genetic markers include mutations in the patatin-like phospholipase domain-containing 3 (PNPLA3) gene, the transmembrane 6 superfamily member 2 (TM6SF2) gene, and the apolipoprotein B (ApoB) gene.
- PNPLA3: Variants in the PNPLA3 gene, particularly the I148M mutation, are strongly linked to hepatic fat accumulation and inflammation. This mutation, prevalent across various ethnic groups, alters the enzyme's function in lipid metabolism, leading to increased fat storage in liver cells. The I148M variant has been associated with a higher risk of developing NAFLD and its progression to non-alcoholic steatohepatitis (NASH) and fibrosis.
- TM6SF2: The TM6SF2 gene, involved in the regulation of very low-density lipoprotein (VLDL) secretion, has a significant polymorphism (rs58542926 C>T) leading to hepatic steatosis and fibrosis. The TM6SF2 E167K variant impairs the secretion of VLDL particles, resulting in lipid accumulation within the liver. This mutation's prevalence varies among ethnicities, with a higher occurrence in Caucasians, and is associated with increased susceptibility to liver damage in lean individuals.
- ApoB: Mutations in the ApoB gene, crucial for lipid metabolism, are also associated with lean NAFLD. These genetic variants affect the assembly and secretion of apolipoprotein B-containing lipoproteins, leading to lipid accumulation and oxidative stress in the liver. ApoB gene variants contribute to the development of hepatic steatosis and progression to more severe liver disease.
The pathogenesis of lean NAFLD involves multiple mechanisms beyond genetic predispositions. These include altered lipid metabolism, oxidative stress, and mitochondrial dysfunction. Genetic variants in PNPLA3, TM6SF2, and ApoB disrupt normal lipid processing and storage in the liver, leading to steatosis and inflammation. Additionally, oxidative stress from accumulated lipids causes mitochondrial damage and further exacerbates liver injury. The interplay between genetic factors and these metabolic pathways drives the progression of liver disease in lean individuals.
Identifying genetic markers for lean NAFLD can facilitate early diagnosis and personalized treatment approaches. Current treatments for NAFLD primarily target metabolic syndrome components, such as insulin resistance and obesity, which may not be effective for lean NAFLD patients. Understanding the specific genetic and molecular mechanisms underlying lean NAFLD can lead to the development of targeted therapies that address the unique pathophysiology of the condition.
Lean NAFLD represents a distinct clinical entity with unique genetic and metabolic underpinnings. Increased awareness and research into the genetic markers and mechanisms are essential for improving diagnosis and management strategies. Future studies should focus on developing specific treatments tailored to the genetic profiles of lean NAFLD patients. By elucidating the genetic and molecular pathways involved, we can improve outcomes for individuals with this challenging variant of NAFLD.
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https://www.xiahepublishing.com/2310-8819/JCTH-2023-00252
The study was recently published in the Journal of Clinical and Translational Hepatology.
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