Nonalcoholic fatty liver disease (NAFLD) is becoming a global threat in the healthcare industry, with more than a quarter of the world’s population affected.
Researchers now believe that certain gene variants could be encouraging the development of this condition.
Novel therapeutic treatment options targeting specific gene expressions could be the most effective way to handle NAFLD.
Read more about personalized treatment options for NAFLD and the different therapeutic treatments to look forward to in the future to handle fatty liver.
Genetic ancestry tests are becoming increasingly popular. While your DNA can be used to learn about your roots, did you know that it can also reveal important things about your health risks and wellness aspects? This allows you to take proactive measures for health conditions, even before the symptoms appear, thereby preventing it. You can upload your DNA data to learn 1,500+ things about your health. Learn more.
Nonalcoholic Fatty Liver Disease: An Overview
Nonalcoholic Fatty Liver Disease (NAFLD) affects a quarter of the global population.
NAFLD is the most commonly occurring liver disease worldwide.
This condition can lead to liver damage and cirrhosis if left untreated.
While some of the common causes of NAFLD are lifestyle-related, researchers now believe that genetic factors also play an essential role in determining the rate of fat deposition and metabolism.
One important gene associated with NFALD is patatin-like phospholipase domain containing 3 (PNPLA3).
What Is The PNPLA3 Gene?
The patatin-like phospholipase domain containing 3 (PNPLA3) gene helps produce a protein named adiponutrin.
Adiponutrin is an essential component of hepatocytes (liver cells) and adipocytes (fat cells).
Role In The Body
The complete role of adiponutrin is not well understood as of now.
However, researchers believe adiponutrin may play a role in fat production and breakdown.
It may also help develop adipocyte cells.
It has been noticed that during periods of fasting, the functioning of the PNPLA3 gene decreased.
PNPLA3 gene’s function increased after a meal.
This suggests that the PNPLA3 gene and the adiponutrin protein also play a role in fat metabolism and storage in the body.
What Is The Role of PNPLA3 In NAFLD?
NAFLD is a condition caused by excessive fat deposition in the liver.
NAFLD is characterized by high levels of serum LDL cholesterol and triglycerides and overweight.
The PNPLA3 gene breaks down triglycerides and other types of fats.
Studies report that mutations in this gene lead to a build-up of triglycerides in the liver.
This, over time, can lead to conditions like liver inflammation, NAFLD, liver cirrhosis, and even liver cancer.
How Does This Gene Affect Fat Breakdown
The PNPLA3 gene is a lipid regulator in the liver cells.
In the liver cells, this gene helps break down triglycerides and convert polyunsaturated fatty acids into their intermediate form, called phosphocholines.
These processes are required to break down fat and eliminate it from the body.
Mutant forms of this gene can therefore affect fat breakdown in the liver and lead to fat accumulation instead.
PNPLA3 As Therapeutic Target For NAFLD and Other Liver Diseases
A particular variant of the PNPLA3 gene was commonly found in those diagnosed with NAFLD.
People with this variant had problems in the regular production of the adiponutrin protein and could not break down fats in their bodies.
Researchers are now trying to target this gene and create therapeutic solutions for different liver diseases.
A 2021 study published by Cherubini and his team explores the idea of using the PNPLA3 as a therapeutic target for slowing down the progression of NAFLD.
According to this study, the PNPLA3 rs738409 C>G variant is the most commonly noted mutation in individuals with NAFLD.
This variant is associated with liver cirrhosis and inflammation and increases the risk of developing hepatocellular carcinoma (liver cancer) by up to 10 times.
Current Therapeutic And Approach
The current generation of therapeutic treatments aims at targeting and disrupting specific protein expressions in the body to achieve favorable results.
Researchers are using liver-targeted Antisense Oligonucleotides (ASOs) as potential treatments for NAFLD.
ASO-based therapies use drugs that bind to the target RNA and modify protein expression through different mechanisms.
Results From Preclinical Trials
There are already preclinical trials conducted using liver-targeted ASOs.
These results report that the PNPLA3 ASO therapy effectively reduced the severity of Nonalcoholic Steatohepatitis (NASH) at all stages.
NASH is a more severe form of NAFLD.
The therapy was able to suppress the actions of the PNPLA3 148M protein successfully.
It helped reduce the intensity of liver inflammation, fibrosis, and fat accumulation.
The next step is the clinical trial, where the researchers would try and treat NASH patients with the PNPLA3 ASO therapy.
The research team hopes to deliver precision medicine to people with NASH using ASO therapy in less than ten years from now.
The team also emphasizes the need to understand the different variants of the PNPLA3 gene and other genes of interest to know how they would react to targeted therapy.
Other Personalized NAFLD Treatment Options Under Investigation
PXL770 is a novel therapeutic drug under investigation to treat NAFLD.
AMP Kinase (AMPK) is an energy sensor associated with lipid metabolism.
The PXL770 drug is a direct AMPK activator and could help people with NAFLD and type-2 diabetes handle their conditions better.
Between 2019 and 2020, a randomized, placebo-controlled, phase 2a study was conducted in 120 patients.
According to the researchers, AMPK activation definitely has the potential to become a pharmacology target in those with NAFLD.
PF-06835919 is a Ketohexokinase (KHK) inhibitor under investigation to treat NAFLD and NASH.
KHK is an enzyme that converts fructose into its next stage, fructose-1-phosphate.
High fructose consumption is one of the reasons for developing NAFLD.
Researchers conducted a randomized phase 2 trial in 2021 with 48 participants.
The research reports that KHK inhibition may be a potential pharmacological target in treating NFALD.
In 2021, an open-label phase II study was conducted to test the effectiveness of PX-104 against liver diseases.
PX-104 is a non-steroidal FXR agonist.
Four-week treatment with PX-104 lowered serum alanine aminotransferase (ALT) and γ-glutamyltransferase (GGT) levels.
These are markers pointing to liver diseases.
Researchers recommend further studies on this medicine to treat NAFLD and NASH.
Summary: PNPLA3 Gene For NAFLD Treatment
- Nonalcoholic fatty liver disease (NAFLD) affects more than 25% of the global population.
- Some of the common causes of developing NAFLD are obesity, consumption of a high-fat diet, type 2 diabetes, and insulin resistance.
- Apart from these cases, specific gene mutations can also increase the chances of developing the condition.
- The patatin-like phospholipase domain containing 3 (PNPLA3) gene produces a protein called adiponutrin that plays a role in fat metabolism.
- Specific variants of this gene can prevent fat breakdown, encourage fat deposition in the liver, and lead to NAFLD.
- The PNPLA3 rs738409 C>G variant is the most observed mutation in people with NAFLD.
- Researchers are trying to create novel liver-targeted Antisense Oligonucleotide (ASO) therapy targeting this specific gene expression.
- Such targeted therapies can prevent the worsening of NAFLD and other liver diseases.
- Other targeted therapies like PXL770, PF-06835919, and PX-104 are under investigation to treat NAFLD and NASH.
Ugonjwa wa ini lisilo la pombe (NAFLD) ni hatari kubwa kwa afya duniani, na zaidi ya asilimia 40 ya watu duniani wameathiriwa. Sasa watafiti wanaamini kwamba tofauti fulani za chembe za urithi zaweza kuchochea ukuzi wa hali hiyo. Njia mpya za matibabu zinazolenga maonyesho maalum ya jeni zinaweza kuwa njia bora ya kushughulikia NAFLD. Soma zaidi kuhusu matibabu ya kibinafsi ya NAFLD na matibabu tofauti ya matibabu ya kutazamia katika siku zijazo kushughulikia ini la mafuta. Uchunguzi wa urithi wa urithi unazidi kupendwa. DNA inaweza kutumika kujifunza kuhusu mizizi yako, lakini pia inaweza kufunua mambo muhimu kuhusu hatari za afya yako. Hii inakuwezesha kuchukua hatua za kujihakikishia hali ya afya, hata kabla ya dalili kuonekana, na hivyo kuzuia. Unaweza kupakia data yako ya DNA na kujifunza zaidi ya mambo 1,500 kuhusu afya yako. Jifunze zaidi. Ugonjwa wa ini la mafuta (NAFLD) huathiri robo ya idadi ya watu duniani. NAFLD ni ugonjwa wa ini unaopatikana kwa kawaida ulimwenguni. Hali hii yaweza kusababisha uharibifu wa ini na ugonjwa wa ini ikiwa haitashughulikiwa. Ingawa baadhi ya sababu za kawaida za NAFLD zinahusiana na mtindo wa maisha, watafiti sasa wanaamini kwamba mambo ya urithi pia hutimiza jukumu muhimu katika kuamua kiwango cha kuweka mafuta na kimetaboliki. NFAD ni jina la jeni linalofanana na patin-like phospholipase domain containing 3 (PNPLA3). Nini Ni Jeni la PNPLA3? Patin-like phospholipase domain yenye jeni PNPLA3 inasaidia kutengeneza protini inayoitwa adiponutrin. Adiponutrin ni sehemu muhimu ya hepatocytes (chembe za ini) na adipocytes (chembe za mafuta). Jukumu la adiponutrin katika mwili Haijulikani vizuri hadi sasa. Hata hivyo, watafiti wanaamini kwamba adiponutrin inaweza kuwa na sehemu katika kutokeza na kuharibika kwa mafuta. Pia yaweza kusaidia kukuza chembe za adipocyte. Katika kipindi cha kufunga, kazi ya jeni PNPLA3 hupungua. PNPLA3 gene inaonekana kuwa na nguvu zaidi baada ya kula. Kwa hivyo, kuna uwezekano kwamba PNPLA3 na adiponutrin zinahusika katika metabolism ya mafuta na kuhifadhi mafuta. Ni nini jukumu la PNPLA3 katika NAFLD? NAFLD ni hali inayosababishwa na mafuta mengi katika ini. NAFLD ni ugonjwa wa kawaida wa kiwango cha juu cha LDL cholesterol na triglycerides na uzito wa ziada. PNPLA3 ni chembe ya urithi inayohusika katika kuharibu triglycerides na aina nyingine za mafuta. Uchunguzi unaripoti kwamba mabadiliko katika jeni hilo husababisha triglycerides kujilimbikizia katika ini. Hii, kwa muda, inaweza kusababisha hali kama vile uvimbe wa ini, NAFLD, cirrhosis ya ini, na hata kansa ya ini. Jinsi Gene hii Inavyoathiri Uharibifu wa Mafuta: PNPLA3 ni jeni linaloongoza lipid katika chembe za ini. Katika chembe za ini, jeni hii husaidia kuvunja triglycerides na kubadilisha asidi za mafuta zisizo na unyevu katika fomu yao ya kati, inayoitwa phosphocolines. Utaratibu huo unahitajika ili kuvunja mafuta na kuyaondoa mwilini. Kwa hiyo, aina zilizobadilika za jeni hilo zinaweza kuathiri uharibifu wa mafuta katika ini na kusababisha mkusanyiko wa mafuta. PNPLA3 kama lengo la matibabu kwa NAFLD na magonjwa mengine ya ini Aina fulani ya jeni ya PNPLA3 iligunduliwa kwa kawaida kwa wale waliogunduliwa na NAFLD. Watu walio na aina hii ya ugonjwa walikuwa na matatizo katika uzalishaji wa kawaida wa protini ya adiponutrin na hawakuweza kuvunja mafuta katika miili yao. Sasa watafiti wanajaribu kuathiri jeni hilo na kutengeneza tiba za magonjwa mbalimbali ya ini. Uchunguzi uliochapishwa na Cherubini na timu yake unachunguza wazo la kutumia PNPLA3 kama lengo la matibabu kwa kupunguza maendeleo ya NAFLD. Kwa mujibu wa utafiti huu, PNPLA3 rs738409 C1G ni mutation ya kawaida zaidi katika watu wenye NAFLD. Aina hii ya saratani huunganishwa na cirrhosis ya ini na uvimbe na huongeza hatari ya kuendeleza kansa ya hepatocellular (ukosefu wa utambuzi wa ini) hadi mara 10. Tiba ya sasa na mbinu ya matibabu ya kizazi cha sasa inakusudia kulenga na kuvuruga maonyesho maalum ya protini katika mwili ili kufikia matokeo mazuri. Watafiti wa utafiti wa kisasa wametumia anti-sense oligonucleotide (ASO) kama dawa ya matibabu ya NAFLD. Tiba ya ASO hutumia dawa ambazo huunganisha na RNA ya lengo na kubadilisha usemi wa protini kupitia taratibu tofauti. Matokeo ya majaribio ya kabla ya kliniki tayari yamefanywa kwa kutumia ASOs zilizolenga ini. Matokeo ya utafiti huo yanaonyesha kuwa matibabu ya PNPLA3 ASO yalipunguza kwa ufanisi ukali wa steatohepatitis isiyo ya pombe (NASH) katika hatua zote. NASH ni aina mbaya zaidi ya NAFLD. Ugonjwa huo ulifanya kazi kwa kuondoa athari za protini ya PNPLA3148M. Ilisaidia kupunguza uvimbe wa ini, fibrosis, na mkusanyiko wa mafuta. Katika hatua ya pili, watafiti watajaribu kutibu wagonjwa wa NASH na matibabu ya PNPLA-3 ASO. Timu ya utafiti inatarajia kutoa dawa sahihi kwa watu wenye NASH kwa kutumia tiba ya ASO katika chini ya miaka kumi kutoka sasa. "Timu hiyo pia inasisitiza haja ya kuelewa tofauti za jeni la PNPLA3 na jeni nyingine za kupendeza kujua jinsi watakavyoitikia tiba inayolenga.""" PXL-770 ni dawa mpya ya matibabu inayochunguzwa kutibu NAFLD. AMP kinase (AMPK) ni sensorer ya nishati inayohusishwa na kimetaboliki ya lipid. Dawa ya PXL-770 ni kichocheo cha moja kwa moja cha AMPK na inaweza kusaidia watu wenye NAFLD na ugonjwa wa kisukari wa aina ya 2 kusimamia hali zao vizuri. Katika kipindi cha miaka ya 2019 na 2020, utafiti wa awamu ya 2a uliopangwa kwa nasibu, uliodhibitiwa na placebo, ulifanywa kwa wagonjwa 120. Kwa mujibu wa watafiti, uanzishaji wa AMPK una uwezo wa kuwa lengo la dawa kwa wale walio na NAFLD. PF68935919 ni kizuizi cha K-H2O kinase (KHK) kinachotathminiwa kutibu NAFLD na NASH. KHK ni enzyme ambayo hubadilisha fructose kuwa hatua yake inayofuata, fructose-1-phosphate. Matumizi ya fructose ya juu ni mojawapo ya sababu za kuambukizwa NAFLD. Watafiti walifanya jaribio la awamu ya pili la randomized mnamo 2021 na washiriki 48. Utafiti huo unaripoti kwamba kuzuia KHK kunaweza kuwa lengo la dawa katika kutibu NFALD. Katika mwaka wa 2021, utafiti wa awamu ya pili wa wazi ulifanywa ili kupima ufanisi wa PX-104 dhidi ya magonjwa ya ini. PX-104 ni agonist ya XR. Ugonjwa wa PX-104 ulipunguza viwango vya seramu vya alanine aminotransferase (ALT) na glutamyltransferase (GGT). Hizi ni alama zinazoonyesha magonjwa ya ini. Watafiti wanapendekeza masomo zaidi juu ya dawa hii kutibu NAFLD na NASH. PNPLA3 Gene kwa matibabu ya NAFLD - ugonjwa wa ini la mafuta (NAFLD) huathiri zaidi ya 25% ya idadi ya watu duniani. Baadhi ya sababu za kawaida za NAFLD ni obesity, ulaji wa chakula chenye mafuta mengi, ugonjwa wa kisukari wa aina ya 2, na upinzani wa insulini. - Mbali na visa hivi, mabadiliko ya chembe za urithi hususa yanaweza pia kuongeza uwezekano wa kuambukizwa ugonjwa huo. Patin-like phospholipase domain yenye 3 (PNPLA3) gene hutengeneza protini inayoitwa adiponutrin ambayo ina jukumu katika kimetaboliki ya mafuta. Aina fulani za jeni hilo zinaweza kuzuia mafuta yasivunjike, kuchochea mafuta kuhifadhiwa kwenye ini, na kusababisha ugonjwa wa NAFLD. PNPLA3 rs738409 C1G ni aina ya mutation ya kawaida ya ugonjwa wa NAFLD. Watafiti wanajaribu kuunda tiba mpya ya Antisense Oligonucleotide (ASO) inayolenga ini inayolenga usemi huu maalum wa jeni. - Matibabu hayo ya kulenga yanaweza kuzuia NAFLD na magonjwa mengine ya ini yasizidi kuwa mabaya. Tiba nyingine za kulenga kama vile PXL-770 na PX-104 zinapimwa kwa ajili ya matibabu ya NAFLD na NASH.