Related Experiment Video
Updated: Jan 16, 2026
07:03
Author Spotlight: Establishing MASLD Cell Models for Investigating Disease Mechanisms and the Lipid-Lowering Effects of Koumiss
Published on: July 19, 2024
1.6K
PNPLA3-I148M is a neomorph that interferes with two primary hepatic triglyceride clearance pathways
David J Sherman1, Lei Liu2, Edward L LaGory2
1Research and Development, Amgen, Thousand Oaks, CA 91320, USA.
Cell Reports
|October 5, 2025
Summary
The PNPLA3-I148M variant, a major genetic risk for fatty liver disease, impairs the secretion of apolipoprotein B (ApoB) and very-low-density lipoprotein (VLDL). This occurs by altering lipid composition, hindering VLDL production and clearance.
Area of Science:
- Hepatology and Genetics
- Molecular mechanisms of liver disease
Background:
- The PNPLA3-I148M variant is the leading genetic risk factor for fatty liver disease globally.
- The precise molecular mechanisms by which I148M contributes to fatty liver disease pathogenesis remain incompletely understood.
Purpose of the Study:
- To elucidate the cellular and molecular mechanisms by which the PNPLA3-I148M variant promotes fatty liver disease risk.
- To investigate the impact of I148M on apolipoprotein B (ApoB) and very-low-density lipoprotein (VLDL) secretion and biogenesis.
Main Methods:
- Utilized human hepatoma cells engineered to express endogenous I148M.
- Employed primary hepatocytes and mouse models for in vivo validation.
- Performed lipidomic profiling to analyze cellular lipid composition.
- Investigated the role of ABHD5/CGI-58 and PNPLA2 in modulating I148M effects.
Main Results:
- The PNPLA3-I148M variant significantly impairs cellular secretion of ApoB and VLDL.
- I148M alters lipid metabolism, shifting from phosphatidylcholine to triglycerides, reducing membrane fluidity and VLDL biogenesis.
- Overexpression of ABHD5/CGI-58 rescues ApoB secretion in I148M cells, while CGI-58 or PNPLA2 knockdown mimics I148M.
- The observed effects are not due to a loss-of-function of wild-type PNPLA3.
Conclusions:
- PNPLA3-I148M acts as a neomorphic variant exacerbating fatty liver disease risk.
- I148M impedes hepatic triglyceride clearance through simultaneous disruption of lipolysis and VLDL secretion pathways.
- These findings highlight novel therapeutic targets for managing fatty liver disease associated with PNPLA3 variants.
Related Concept Videos
01:09Hepatic Drug Clearance: Restrictive and Nonrestrictive Clearance
477
Hepatic clearance refers to the volume of blood cleared of a drug by the liver per unit of time. It plays a crucial role in drug metabolism and elimination. While hepatic clearance is commonly estimated by subtracting renal clearance from total body clearance, other pathways, such as pulmonary or biliary clearance, may also contribute. However, these pathways are generally less significant than hepatic and renal clearance.
Most drugs undergo restrictive clearance, which is proportional to the...
Most drugs undergo restrictive clearance, which is proportional to the...
477
01:26Effect of Hepatic Disease on Pharmacokinetics: Drug Dosing and Hepatic Blood Flow
212
Chronic liver disease significantly impacts drug metabolism due to alterations in hepatic blood flow and enzyme accessibility. This disruption affects the body's pharmacokinetics—the movement and processing of drugs within the system. Key enzymes crucial for metabolizing medications become less accessible, changing how drugs are processed and utilized. Furthermore, liver disease influences the synthesis of plasma proteins, such as albumin and globulins, which play critical roles in drug...
212
01:07Physiological Pharmacokinetic Models: Incorporating Hepatic Transporter-Mediated Clearance
277
Drug transporters are critical in drug absorption, distribution, and excretion processes. They should be included in physiological-based pharmacokinetic (PBPK) models, which help predict human drug disposition. However, predicting this is challenging during drug development, especially when liver transport is involved. However, with a realistic representation of body transport processes, an accurate model may be possible.
A recent model describes pravastatin's hepatobiliary excretion,...
A recent model describes pravastatin's hepatobiliary excretion,...
277
01:14Hepatic Drug Clearance: Role of Transporters
296
In the liver and bile canaliculi, influx and efflux transporters modification can influence intrinsic clearance. Transporters play a significant role in moving drugs within liver cells. Elaborate models, such as the Biopharmaceutical Classification System (BCS), are essential to relate transporters to drug disposition. This system categorizes drugs into four classes based on solubility and permeability, providing insights into elimination routes and the effects of transporters following oral...
296
01:16Hepatic Drug Excretion: Influencing Factors
524
The biliary system of the liver, crucial for bile secretion and drug excretion, comprises intrahepatic bile ducts that merge to form the common hepatic duct. This duct, carrying hepatic bile, combines with the cystic duct, draining the gallbladder and forming the common bile duct, which empties into the duodenum. Bile, produced by hepatic cells lining the bile canaliculi, is composed primarily of water, bile salts, pigments, electrolytes, and lesser amounts of cholesterol and fatty acids. Bile...
524
01:20Pharmacokinetics in Obese Patients: Drug Metabolism and Excretion
166
Drug metabolism, a critical process in the liver, involves two primary phases: Phase I reactions and Phase II conjugation. Obesity introduces significant alterations in this metabolic process, primarily due to fatty infiltration of the liver, leading to conditions such as nonalcoholic fatty liver disease (NAFLD). This condition can modify the activities of both Phase I and II enzymes, impacting how drugs are metabolized in obese patients.Phase I metabolism sees variable effects across...
166