Millions of years ago, when our ancestors hunted and roamed the jungle, vexed by a beast that got

away so fast, moaned helplessly for the missed meal, they may never have imagined that their

descendants would one day worry about consuming too much fat, burdening their livers. Fatty liver

disease is one of the most common diseases in the world nowadays, affecting 30% of the adult

population, roughly 25% non-alcoholic and 5% alcoholic. Fatty liver disease normally exhibits no

symptoms at early stages and is often detected during routine physical examinations. However, without

appropriate management and treatment, it can gradually progress to steatohepatitis (fatty liver with cell

injury and inflammations), cirrhosis (liver fibrosis with built-up scars), and hepatocellular carcinoma (a

form of liver cancer). Obese and diabetic populations are more susceptible to develop fatty liver disease,

further exacerbating their metabolic dysfunctions and medical conditions.

A healthy liver can metabolize lipids in specific pathways, primarily involving the uptake of circulating

fatty acids, de novo lipogenesis, disposing lipids through oxidation (in the mitochondria, peroxisomes

and cytochromes), and exporting lipids as minuscule particles. When the accumulation of lipid in liver

cells surpassed their disposal capacity, large lipid drops can form and are difficult for the cell to

breakdown and eliminate. To maintain efficient lipid metabolism, phospholipids, a main component of

cell membranes, are in constant demand and undergo rapid turnover in cells. This process resembles

tearing down old walls in a house and immediately constructing new ones, necessitating the

participation of many commanders (pathway regulators). Lysophospholipids are one of the regulators.

Lysophospholipids are a group of highly bioactive intermediate cell products that play a critical role in

maintaining cellular abundancy of phospholipids, facilitating the formation of tiny lipid particles, and

preventing the formation of large lipid drops. However, a challenge arises: lysophospholipids are

partially water soluble and primarily present in body fluids, such as blood, how can they penetrate the

highly hydrophobic cell membranes to exert their functions?

Liver cells are sophisticated and swift operators. They know how to make gateways in the walls to allow

essential molecules in. In scientific phrase, liver cells can express specific transporter molecules on the

cell membranes. One of these transporters, with a quite complicated name, major facilitator superfamily

domain containing 2A (Mfsd2a), functions as gateways for lysophospholipids to enter liver cells. Mfsd2a

was identified by the David L. Silver’s team from Duke-NUS Medical School in Singapore in 2012. Mfsd2a

is mainly distributed in blood–brain barrier, facilitating the transportation of DHA into brain cells. It was

not considered to be a fundamental component of healthy livers. However, researchers observed that

the expression of Mfsd2a increased substantively in patients with fatty livers or in mice challenged with

high-fat diet. When Mfsd2a was selectively deleted from mouse livers, those unlucky rodents developed

severe steatohepatitis and fibrosis after feeding high-fat diet for 2~16 weeks, associated with reduced

beneficial hepatic phospholipids. Despite Mfsd2a’s potent role in transporting lysophospholipids to

assist liver cells to “return to homeostasis”, its functions require the regulation from glucocorticoid

receptor (dexamethasone is the most common glucocorticoid).

These significant research findings were published in the Journal of Clinical Investigation on September

1, 2023, under the title of " Blood-derived lysophospholipid sustains hepatic phospholipids and fat

storage necessary for hepatoprotection in overnutrition” (https://www.jci.org/articles/view/171267).

The journal of Clinical Investigation is renowned for its stringent selection process, long review time, and

numerous review comments. However, this groundbreaking discovery, supported by a solid amount of

high-quality clinical data, was selected as the cover story of the 133rd issue, owing to its novelty and

inspiration.

Unlike its central character in brain cells where DHA transportation is constantly required, Mfsd2a acts

more like temporary emergency gateways in liver cells. These gateways are scarce under normal

situations but are swiftly “constructed” when liver cells encounter overnutrition. Moreover, Mfsd2a was

exclusively expressed on the basolateral side of periportal liver cells, meaning the gateways open to the

very front line to receive nutrients from blood vessels. The Silver team has also proposed the

mechanism by which Mfsd2a transports lysophospholipids into cells in a Na+-dependent manner:

Mfsd2a maintains a V-shape structure and the outward-facing configuration allows it to receive

lysophospholipids from the bloodstream. Once lysophospholipids are inserted into the hydrophobic cleft

of Mfsd2a, the gateways undergo a conformational change from outward-facing to inward-facing. As a

result, lysophospholipids are transferred from the outer leaflet to the inner leaflet and successfully

transported to the interior of liver cells.

Currently, there are no FDA-approved medications for fatty liver disease, except for vitamin E and

pioglitazone, which are recommended for nonalcoholic steatohepatitis (NASH) and diabetes. This

discovery can provide important insight on pharmaceutical development aimed at controlling fatty liver

disease. These insights encompass various aspects, such as, the development of lysophospholipid-rich

dietary supplements, the creation of lysophospholipid-mimicking molecules binding to Mfsd2a, the

exploration of GR-akin molecules specific for Mfsd2a, and mRNA vaccines or nano particles to

overexpress Mfsd2a in obese or diabetic patients to restore dysfunctional Mfsd2a.

Nonetheless, fatty liver disease is fundamentally related to lifestyles. It is more essential to shift toward

healthy lifestyles rather than investing thousands of dollars in medications. Even if you do not need to

chase for a meal like our ancestors did, it is advisable to engage in regular physical activity several times

each week. This is beneficial not only for your liver but for all your organs.