High-protein diets and metabolic dysfunction-associated steatotic liver disease: A double-edged sword in liver health

Abstract

Metabolic dysfunction-associated steatotic liver disease (MASLD) is among the most prevalent chronic liver conditions globally and is closely linked with a range of metabolic disorders. Recently, the high-protein diet (HPD) has garnered attention for its potential benefits in weight management and metabolic health; however, its impact on MASLD remains a subject of debate. This article provided a systematic review of epidemiological studies, clinical trials, and foundational research concerning the role of HPD in MASLD. It examined the mechanisms by which HPD influences liver metabolism, inflammatory responses, and gut microbiota in patients with MASLD and assessed their clinical efficacy. The review revealed that HPD exerts dual effects on MASLD, contingent upon the protein source and consumption levels, and plant-based proteins conferred metabolic advantages. Therefore, it is advised that patients with MASLD prioritize plant-based proteins while moderating animal protein intake. Future research should aim to elucidate the mechanisms underlying HPDs and deploy personalized nutrition approaches that integrate genomic, proteomic, metabolomic, and microbiome profiles to predict individual responsiveness to specific protein sources, thereby enabling precision dietary algorithms for MASLD prevention and treatment.

Key Words: High-protein diets; Metabolic dysfunction-associated steatotic liver disease; Diet; Mechanism; Clinical trial

Core Tip: High-protein diets have dual effects on metabolic dysfunction-associated steatotic liver disease, depending on protein source and amount. Plant-based proteins may benefit liver metabolism, inflammation, and gut microbiota, whereas excessive animal proteins could worsen outcomes. Patients with metabolic dysfunction-associated steatotic liver disease should favor plant proteins and limit animal proteins; personalized dietary strategies require further mechanistic research.

INTRODUCTION

Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly referred to as nonalcoholic fatty liver disease (NAFLD), encompasses a spectrum of liver disorders acquired through metabolic stress[1]. MASLD represents a substantial public health concern and is now acknowledged as the most widespread chronic liver disease worldwide, impacting over 30% of the adult population[2,3]. Histopathologically, MASLD manifests as a continuum of disease states, including metabolic dysfunction-associated fatty liver, metabolic dysfunction-associated steatohepatitis (MASH), and associated fibrosis and cirrhosis[4]. The condition is intricately associated with various metabolic derangements, such as central obesity, hypertension, dyslipidemia, and impaired glucose tolerance. These metabolic disturbances not only exacerbate the progression of liver disease but also elevate the risk of developing other severe health complications, including cardiovascular diseases and specific malignancies[1,5]. Despite its increasing prevalence therapeutic options for MASLD remain limited beyond lifestyle interventions, underscoring the critical need for the development of effective pharmacological treatments and strategies[6,7].

Recent studies have demonstrated a significant correlation between diet quality, physical activity, and the prevalence of MASLD[8-11]. MASLD is characterized by inflammation, metabolic disturbances, and intestinal microbiota disorders, which result from hepatic steatosis caused by the accumulation of adipose tissue originating from the gastrointestinal tract and within hepatocytes[12]. The accumulation of lipids in the liver is primarily attributed to diets high in added sugars and saturated fats, leading to excessive lipid deposition[13]. Adherence to healthier dietary patterns has been associated with a reduced risk of MASLD with vegetables and whole grains being the primary contributors to this association, and promoting healthy eating patterns may therefore be beneficial in preventing MASLD[14].

Within the general population of the United States, individuals with MASLD are more frequently adhering to special diets, suggesting an increased awareness and interest in utilizing dietary modifications to improve health outcomes. Certain nutritional factors, such as vitamins E and K, may offer protective effects against MASLD, but increased intake of macronutrients, including carbohydrates, cholesterol, total saturated fatty acids, and overall caloric intake, may facilitate the progression of MASLD[15]. Moreover, an unhealthy diet plays a crucial role in the development of obesity, a prominent and widespread risk factor for MASLD. For instance, a diet high in fat can induce MASLD through mechanisms such as fat accumulation, mitochondrial dysfunction, inflammation, and disorders of the hepato-intestinal axis[16,17].

High-protein diets (HPD) have gained modern popularity in the general population for its putative benefits in weight control and fat reduction. The International Nutrition Association recommends a protein intake of 0.8 g/kg/day for healthy adult individuals. The National Health and Nutrition Examination Survey data indicate that current mean protein intakes in the United States already reach 1.2-1.4 g/kg/day, comfortably exceeding this benchmark[18]. Although there is no universally accepted definition for an HPD, most definitions delineate a range from 1.2 g/kg/day to 2.0 g/kg/day with intakes exceeding 1.5 g/kg/day typically classified as high protein[19]. Such diets may mitigate the increased lipid absorption facilitated by Lactobacillus, thereby preventing fat mass accumulation following a dieting phase[20,21]. Furthermore, in comparison with the Mediterranean diet, HPDs have demonstrated greater efficacy in improving insulin sensitivity and reducing glycemic variability, which can be advantageous for individuals with diabetes or those at risk of developing the condition[22].

Nonetheless, it is crucial to acknowledge the potential adverse effects associated with HPD. High protein consumption may lead to intraglomerular hypertension, which can result in renal hyperfiltration, glomerular damage, and the onset of proteinuria. There exists a potential risk that prolonged high protein intake may contribute to the development of de novo chronic kidney disease (CKD)[23]. The recent Kidney Disease: Improving Global Outcomes commentary clearly states that high animal protein is an independent risk for diabetes complicated with CKD, emphasizing that the source of protein is more important than the total amount[24]. Estimated glomerular filtration rate < 60 mL/minute/1.73 m² is regarded by most guidelines as a “high-protein potential risk area,” and it is recommended to start protein restriction[18]. Furthermore, HPD has been associated with increased cardiovascular risk due to the activation of mechanistic target of rapamycin (mTOR) in macrophages that subsequently inhibits mitophagy[25]. Despite these concerns HPD can be beneficial for weight management and metabolic health enhancement. It is essential, however, to carefully balance these benefits against the potential risks, particularly for individuals with pre-existing conditions, and to customize dietary plans to meet individual needs.

Recent studies have indicated that a healthy diet combined with planned exercise constitutes the most fundamental treatment for most MASLD. Optimizing dietary composition, particularly protein intake, alongside increasing physical activity, has been shown to be advantageous for liver health and the management of metabolic complications. In light of this, the present article examined the pathogenesis and influencing factors of MASLD and reviewed recent research on the relationship between HPD and MASLD. The aim was to generate novel insight for the prevention and treatment of MASLD and to provide a foundation for precise nutritional intervention strategies.

SPECIAL CORRELATION BETWEEN DIET AND MASLD

Currently, diverse dietary patterns have been identified to exert varying effects on MASLD. The Western diet, characterized by a high intake of processed foods, refined cereals, high-sugar products, high-fat dairy products, and processed meats, is correlated with an elevated risk of MASLD[26]. For example, research has demonstrated that a diet rich in fats and fructose results in increased body and liver weight, glucose intolerance, and liver abnormalities, which are indicative of a transitional state between fatty liver and liver fibrosis[27,28]. Additionally, the Western diet, which is high in monounsaturated fats, may exacerbate oxidative damage and hepatic steatosis during the early stages of MASLD, potentially contributing to its progression[29]. This dietary pattern is also associated with an increased production of proinflammatory cytokines and a reduction in anti-inflammatory cytokines.

Conversely, the traditional Mediterranean diet, which emphasizes the consumption of olive oil, nuts, fruits, vegetables, legumes, and fish while limiting the intake of red meat and sweets, has been demonstrated to be advantageous for patients with MASLD. It can significantly lower total cholesterol and liver stiffness, mitigate inflammation induced by oxidative damage, and attenuate toll-like receptor 4-mediated hepatic inflammation[30]. Insulin resistance is currently acknowledged as a fundamental pathogenic feature of MASLD and a critical contributor to the progression of hepatic inflammation[31]. The Mediterranean diet has been identified as the most effective dietary intervention for alleviating postprandial hyperglycemia and improving insulin sensitivity without necessitating weight loss[27]. Furthermore, research conducted by Yaskolka Meir et al[32] has demonstrated that the green-Mediterranean diet, characterized by reduced consumption of red and processed meats and increased intake of green plants and polyphenols, results in a two-fold reduction in intrahepatic fat compared with other healthful dietary approaches and decreases the prevalence of MASLD by 50%.

Another promising dietary approach is intermittent fasting, often termed “the next significant trend in weight management,” which is also known as periodic prolonged fasting or intermittent calorie restriction. Common variations of intermittent fasting involve fasting for up to 24 h once or twice a week with unrestricted eating on non-fasting days[32,33]. The 5:2 intermittent fasting regimen has been shown to ameliorate MASH and fibrosis while also reducing the risk of hepatocellular carcinoma through the activation of peroxisome proliferator-activated receptor alpha and phosphoenolpyruvate carboxykinase 1[34].

In terms of protein characteristics, the Western diet is predominantly characterized by a high intake of animal protein, primarily derived from processed meats and dairy products[35,36]. Conversely, the Mediterranean diet is recognized as a health-promoting dietary pattern, noted for its numerous health benefits. It is distinguished by the consumption of moderate amounts of fish and seafood, which are rich in omega-3 fatty acids and provide high-quality protein. Additionally, poultry and eggs are consumed in moderate quantities while red meat and processed meats are limited[37,38] (Figure 1).

Figure 1 Comparative effects of dietary patterns on hepatic metabolism, inflammation, and metabolic dysfunction-associated steatotic liver disease risk. The Western diet, characterized by high intake of ultra-processed foods, red meat, and added sugars, exacerbates hepatic steatosis, glucose intolerance, and bodyweight gain. This dietary pattern promotes proinflammatory cytokine release, nuclear factor kappa B signaling, and toll-like receptor 4-mediated inflammation, leading to oxidative stress, liver stiffness, and fibrosis. The high-fat/high-fructose diet rapidly increases blood glucose and bodyweight, inducing metabolic dysfunction and hepatic pathology. Consequently, the risk of metabolic dysfunction-associated steatohepatitis and hepatocellular carcinoma is markedly increased. In contrast, the Mediterranean diet, rich in monounsaturated fatty acids, omega-3 fatty acids, and polyphenols from nuts, fruits, vegetables, legumes, and fish, enhances insulin sensitivity and reduces hepatic lipid accumulation. Intermittent fasting (5:2 regimen) further augments these protective effects by upregulating phosphoenolpyruvate carboxykinase 1 and peroxisome proliferator-activated receptor alpha, thereby suppressing oxidative damage, inflammatory signaling, and postprandial hyperglycemia. PPARα: Peroxisome proliferator-activated receptor alpha; PCK1: Phosphoenolpyruvate carboxykinase 1; TSC: Tuberous sclerosis complex; AA: Amino acid; mTORC: Mechanistic target of rapamycin complex; MASH: Metabolic dysfunction-associated steatohepatitis; HCC: Hepatocellular carcinoma; NK-κB: Nuclear factor kappa B; TLR4: Toll-like receptor 4; MASLD: Metabolic dysfunction-associated steatotic liver disease; PI3K: Phosphatidylinositol 3-kinase; AKT: AKR mouse thymoma kinase; Rag: Ras-related GTP-binding protein; SLC38A: Solute carrier family 38 member A.

HPD AND ITS MECHANISMS IN MASLD

Recent animal studies have begun to clarify the double-sided role of dietary protein in MASLD. Over the past 10 years, experiments in genetically modified mice and obese rats have shown that precisely dosed high-protein regimens rapidly reduce hepatic lipid stores and improve systemic metabolism. Conversely, some research has revealed that feeding mice with protein intake beyond a threshold, even for as little as 2 weeks, unleashes macrophage and neutrophil activation, spikes circulating liver enzymes, and aggravates steatosis. Investigations using gnotobiotic and sequencing approaches further demonstrate that these dietary manipulations trigger immediate gut microbiota shifts, thereby modulating the microbiota-gut-liver axis and dictating whether the net effect is protection or progression of MASLD (Figure 2).

Figure 2 Animal experiments on the dual roles of high-protein diets in metabolic dysfunction-associated steatotic liver disease development and progression. Compared with diets rich in animal-derived proteins, plant-based protein intake beneficially remodels hepatic lipid metabolism and gut microbiota. Some plant proteins are related to the increase of beneficial bacteria in the intestinal flora, but the intake of plant proteins is usually accompanied by fiber co-ingestion and resistant starch, conducive to the increase of beneficial bacteria. Diets high in animal protein upregulate mechanistic target of rapamycin and sterol regulatory element-binding protein-1c, elevate circulating branched-chain amino acids and homocysteine, and suppress phosphorylation-AMP-activated protein kinase, shifting the balance toward fatty acid biogenesis and away from oxidation, increasing triacylglycerol synthesis, hepatic steatosis, serum liver enzyme levels, and markers of liver injury. Conversely, plant-based proteins expand populations of Bacteroidetes, Prevotella, Akkermansia, and short-chain fatty acid producers while decreasing the relative abundance of Firmicutes, resulting in reduced hepatic fat deposition, ameliorated histological alterations, improved hepatic detoxification capacity, and attenuated systemic inflammation. p-AMPK: Phosphorylation-AMP-activated protein kinase; SREBP-1c: Sterol regulatory element-binding protein-1c; SCFAs: Short-chain fatty acids; mTOR: Mechanistic target of rapamycin; TAG: Triacylglycerol; ROS: Reactive oxygen species.

Beneficial consequences

The latest experimental studies have highlighted the significant advantages of HPD in animal models of MASLD. For example, research by Santos-Sánchez et al[39] demonstrated that legume protein hydrolysate effectively reduces abdominal adiposity and ameliorates MASLD in ApoE(-/-) mice fed a Western diet. Similarly, plant-derived bioactive peptides and protein hydrolysates have been identified for their potential beneficial effects on MASLD-related parameters, likely due to their antioxidant, anti-inflammatory, and lipid-lowering properties[40]. Abbate et al[41] demonstrated that a 12-week administration of protein hydrolysates derived from anchovy waste significantly alleviates the severity of MASLD in ApoE-deficient mice. This finding reinforces the hypothesis that protein hydrolysates can positively influence liver health.

Furthermore, HPD in general has been shown to be more effective in reducing hepatic fat compared with low-protein diets. French et al[42] revealed that HPD effectively mitigates weight gain and food intake while reducing liver fat deposition and enhancing markers of muscle metabolism in obese Zucker rats. Protein derived from beans can diminish hepatic fat deposition and prevent MASLD, and the biological sex of mice determines the amount of beans in the diet required to prevent hepatic lipid accumulation[43]. Collectively, these studies underscore the potential of HPD and related compounds in managing MASLD in animal models, suggesting promising avenues for further research and potential therapeutic strategies for combating this metabolic disorder.

Harmful consequences

Other research has indicated that HPD may have adverse effects on MASLD. For instance, administering diets with exceptionally high protein content to mice for a duration of 2 weeks has been demonstrated to activate macrophages and neutrophils, subsequently resulting in a marked elevation of liver enzymes in the bloodstream and precipitating acute liver injury. This finding implies that HPD may pose a risk of liver damage and be detrimental to MASLD. Additionally, prolonged consumption of HPD has been observed to enhance pathways associated with liver triacylglycerol accumulation and exacerbate hepatic injury markers in rats, suggesting that sustained intake of HPD could contribute to liver damage and potentially aggravate MASLD[44].

Research conducted by Monteiro et al[45] has demonstrated that a diet rich in protein and low in carbohydrates induces cellular and histopathological damage in the livers of laboratory rodents, harming the liver and potentially worsening MASLD. Furthermore, Liao et al[46] identified that within the context of obesity, the upregulation of de novo lipogenesis is a critical feature of MASLD with amino acids playing a crucial role as a major carbon source for hepatic lipogenesis. Low-protein diets have been demonstrated to confer a range of benefits in obese mice, notably preventing excessive body weight gain and reducing hepatic lipid accumulation and subsequent liver damage. This evidence indicates that dietary protein intake may significantly influence the metabolic pathways involved in the development and progression of MASLD.

Special amino acids

The relationship between amino acids and MASLD is intricate and multifaceted. Certain amino acids, such as branched-chain amino acids (BCAAs), have been shown to positively impact liver health. BCAAs have been employed in the treatment of patients with decompensated cirrhosis and have been found to ameliorate hepatic steatosis and liver injury in mice with MASH induced by a choline-deficient high-fat diet[47]. This suggests that BCAAs may play a protective role in certain liver diseases. Conversely, elevated levels of certain amino acids have been associated with an increased risk of liver disease.

For example, a meta-analysis has revealed that individuals with MASLD tend to exhibit higher serum homocysteine levels, which is correlated with a heightened risk of hyperhomocysteinemia, indicating that elevated homocysteine levels may be a risk factor for the development of MASLD[48]. Glutamine, an essential amino acid, has been shown to prevent hepatic lipid accumulation in mice on a high-fat diet by influencing lipolysis and oxidative stress. Zhang et al[49] found that glutamine improved lipid storage, liver damage, and oxidative stress in obese mice on a high-fat diet. However, while glutamine may prevent high-fat diet-induced MASLD in mice, it does not reverse the condition once established. These findings underscore the varied roles amino acids play in MASLD.

While amino acids like BCAAs and glutamine may offer protective effects, elevated levels of others, such as homocysteine, may increase disease risk. The latest research has found that amino acids are the main carbon source for liver fat production and are related to the following multiple pathways, such as leucine-mTOR complex 1 (mTORC1)-sterol regulatory element-binding protein-1c (SREBP-1c), tryptophan-aryl hydrocarbon receptor-interleukin 22, and methionine-homocysteine-endoplasmic reticulum stress branches, etc.

For example, arginine or leucine is sufficient for mTORC1 lysosomal translocation and subsequent nuclear translocation of SREBP1c, leading to fatty acid synthesis in primary hepatocytes[50]. In addition, mTORC1 inhibition (rapamycin) can abolish insulin-induced maturation of SREBP1c and reduce hepatic triglycerides (TG) secretion[51]. Urea-cycle intermediates (arginine, ornithine) are not mere metabolites but mTORC1 agonists driving hepatocyte growth and lipid synthesis. mTORC1 is highly phosphorylated in early MASLD and is accompanied by upregulation of lipid synthesis genes. When entering the nonalcoholic steatohepatitis stage, mTORC1 has a certain protective effect on the initiation and progression of MASH[52].

Additionally, plant protein foods come bundled with 5-15 g fiber/100 g, acting as a major positive confounder. A sensitivity analysis in the 2025 cohort showed the apparent diabetes protection by plant protein lost significance after additionally adjusting for fiber intake[53]. Cellulose can affect the intestinal absorption process. Even if the same amount of leucine is consumed compared with a meal high in animal protein, usually with extremely low fiber, a plant-based protein meal may not be able to rapidly increase the plasma leucine concentration to the threshold for activating mTORC1 in a short period of time. Further research is necessary to elucidate the mechanisms by which amino acids affect liver health and to explore their potential therapeutic applications in MASLD management (Figure 3).

Figure 3 Dietary protein sources and metabolic regulation in metabolic dysfunction-associated steatotic liver disease progression. This schematic illustrates the differential metabolic impacts of plant-derived vs animal-derived dietary proteins on systemic amino acid profiles and hepatic signaling pathways relevant to metabolic dysfunction-associated steatotic liver disease and metabolic dysfunction-associated steatohepatitis. Plant proteins provide higher fiber and lower leucine bioavailability, maintaining plasma leucine < 250 μmol/L. In contrast, animal proteins (low fiber) elevate plasma leucine ≥ 250 μmol/L and increase methionine and tryptophan concentrations. Elevated leucine activates the Rag GTPase-Rheb-GTP axis, thereby stimulating mechanistic target of rapamycin complex 1 signaling and downstream transcriptional programs, including sterol regulatory element-binding protein-1c cleavage and nuclear translocation, promoting de novo lipogenesis. Concurrently, high methionine intake raises homocysteine levels, while arginine and ornithine serve as urea-cycle intermediates that modulate phosphatidylinositol 3-kinase/protein kinase B activity. These changes converge on endoplasmic reticulum stress, signal transducer and activator of transcription 3 and hypoxia inducible factor-1 alpha activation, and interleukin 22 induction, collectively exacerbating hepatic steatosis and inflammation. Conversely, plant-protein-associated lower leucine availability attenuates mechanistic target of rapamycin complex 1-sterol regulatory element-binding protein-1c signaling and favors metabolic dysfunction-associated steatohepatitis attenuation. mTORC1: Mechanistic target of rapamycin complex 1; PI3K: Phosphatidylinositol 3-kinase; AKT: Protein kinase B; AhR: Aryl hydrocarbon receptor; IL22: Interleukin 22; SCAP: Sterol regulatory element-binding protein-cleavage-activating protein; SREBP-1c: Sterol regulatory element-binding protein-1c; ER: Endoplasmic reticulum; GLI1: Glioma-associated oncogene homolog 1; STAT3: Signal transducer and activator of transcription 3; HIF-1α: Hypoxia inducible factor-1 alpha; MASH: Metabolic dysfunction-associated steatohepatitis; Rag GTPase: Ras-related GTP-binding protein; Rheb: Ras homolog enriched in brain.

Gut microbiota

Quantitative and qualitative alterations in the gut microbiota are crucial determinants in the onset and progression of MASLD[54-56]. Animal studies utilizing various microbiome-sequencing platforms and MASLD diagnostic tools have consistently supported the causal involvement of the intestinal microbiota in hepatic steatosis[57]. In a controlled study conducted by Liu et al[58], rats fed an HPD showed a notable increase in Bacteroidetes, Prevotella, Oscillospira, and Sutterella along with a concurrent decrease in the Firmicutes phylum. Interestingly, hepatic steatosis induced by high-fat and high-sugar diets was independent of total caloric intake, suggesting that these compositional changes are mechanistic drivers of MASLD pathogenesis.

Plant protein is usually consumed together with high fiber and resistant starch. These components are the main driving factors for the enrichment of beneficial bacteria such as Bacteroidetes. A diet pattern that increases plant intake promotes changes in the intestinal flora[59]. Shi et al[60] demonstrated that a high-protein quinoa-enriched yogurt restored gut microbial equilibrium, activated the microbiome-gut-liver axis, and subsequently mitigated hepatic steatosis in MASLD by inhibiting lipogenesis and enhancing fatty acid oxidation. Furthermore, these dietary interventions are believed to exert protective effects through microbiome-derived metabolites that function as epigenetic effectors, influencing intestinal permeability, insulin signaling pathways, and immune responses, thereby mitigating the progression of MASLD[61]. Cumulatively, emerging evidence suggests that targeted dietary interventions involving specific micronutrients or bioactive compounds can alter gut microbial composition, thereby attenuating the disease trajectory of MASLD.

CLINICAL EVIDENCE ON HPD IN MASLD

Rapidly expanding clinical evidence now frames dietary protein as both ally and adversary in MASLD. Across randomized controlled trials and prospective cohorts, higher-protein diets, especially those rich in plant or dairy sources, consistently reduce hepatic fat, preserve lean mass, and improve glycemic control. Yet when the dominant sources shift toward processed red meats and specific amino-acid profiles, the same macronutrient intensifies histological activity, necroinflammation, and hepatic iron dysregulation. Importantly, it appears to be tied less to absolute quantity than to quality, highlighting the need for a deliberate, source-focused strategy when leveraging protein to prevent or manage MASLD (Figure 4).

Figure 4 Clinical evidence of protein source and type on metabolic dysfunction-associated steatotic liver disease outcomes across study designs. High-protein diets, especially those rich in animal-derived proteins, worsen metabolic dysfunction-associated steatotic liver disease by accelerating hepatic lipid accumulation, disturbing hepatic iron homeostasis, and generating metabolic dysfunction-associated steatotic liver disease-inducing amino acid metabolites that alter intestinal flora composition, heightening overall mortality in patients with cirrhosis. On the contrary, other studies have found a high-protein diet improves insulin sensitivity and rebalances gut microbial ecology, conferring a beneficial hepatic metabolic profile. MASLD: Metabolic dysfunction-associated steatotic liver disease; T2D: Type 2 diabetes.

Beneficial consequences

A considerable body of evidence from human studies indicates that HPD may have beneficial effects on MASLD. For example, a randomized controlled trial by Feng et al[62] proved that diets with high protein and lower carbohydrate could contribute to reducing liver steatosis and MASLD. A multicenter randomized controlled trial conducted in China[63] demonstrated that compared with a normal or low-protein diet HPD significantly reduced liver fat content, offering additional benefits for MASLD outcomes. However, it is crucial to acknowledge that excessive protein intake may also lead to elevated serum creatinine levels.

A case-control study by Chaturvedi et al[64] confirmed that a protein-rich diet provided a protective effect against MASLD. This finding suggests that increasing protein intake in the daily diet may serve as a preventive measure against the development of MASLD. Daftari et al[65] conducted a prospective cohort study and demonstrated that a higher intake of total protein and milk protein, coupled with a lower intake of animal protein, was associated with a reduced risk of mortality in patients with liver cirrhosis. This finding underscores the significance of protein type, suggesting that plant-based and dairy proteins may confer greater benefits than animal proteins.

In an analysis of individuals aged 40-69 years, Lee et al[66] identified a significant negative correlation between higher dairy protein intake and the risk of developing MASLD in both males and females. Further investigation indicated that regular consumption of milk and other dairy products may contribute positively to MASLD prevention. Moreover, HPD was found to be more effective in reducing hepatic fat compared with a low-protein diet despite lower levels of autophagy and fibroblast growth factor 21. The data suggest that this reduction in liver fat is primarily attributable to the suppression of fat uptake and lipid biosynthesis pathways[67].

A randomized controlled trial revealed that a protein-rich diet was associated with the maintenance of lean body mass and a reduction in hepatic lipid accumulation[68]. The evidence indicates that HPD may be instrumental in preserving muscle mass while reducing liver fat deposition, thereby benefiting metabolic regulation in individuals with MASLD. Furthermore, a randomized controlled trial involving individuals with type 2 diabetes who maintained stable body weight demonstrated that a low-carbohydrate, HPD significantly improved glycemic control as reflected by enhanced glycated hemoglobin levels while simultaneously decreasing liver fat accumulation[69].

A case-control study by Khazaei et al[70] found that a higher proportional contribution of dietary protein to total energy intake was associated with lower MASLD risk, and this inverse gradient was accentuated when the incremental protein was derived predominantly from plant rather than animal sources. In a prospective study of individuals with type 2 diabetes, it was found that diets high in protein, regardless of whether the protein was derived from animal or plant sources, substantially reduced liver fat content independently of body weight changes. Additionally, these HPDs were associated with a decrease in markers indicative of hepatic necroinflammation[71]. Collectively, these findings underscore the potential of HPD to play a pivotal role in the management of MASLD by mitigating liver fat accumulation and enhancing metabolic control.

Harmful consequences

The relationship between HPD and MASLD is characterized by complexities and potential adverse effects. Empirical evidence suggests that a high protein intake, particularly when it constitutes 17.3% or more of daily caloric consumption, is associated with increased histological disease activity in patients with MASLD. This association is primarily influenced by specific amino acids, including serine, glycine, arginine, proline, phenylalanine, and methionine[72]. Research conducted by Wehmeyer et al[73] indicated that MASLD was more strongly correlated with an overall excessive caloric intake rather than a specific dietary pattern. Notably, individuals with MASLD tended to consume a greater amount of protein per 1000 kcal of energy intake compared with those without the condition. This observation implies that while dietary composition is significant, the quantity of protein intake also plays a crucial role in the onset and progression of MASLD.

Furthermore, the source of animal protein appears to have varying effects on liver health in individuals with MASLD and obesity. Specifically, the consumption of processed meats has been associated with alterations in hepatic iron concentration, which may have deleterious effects. In contrast, the consumption of fish has been linked to enhanced ferritin levels, which are advantageous for liver health. These findings highlight the necessity of considering not only the quantity but also the quality and type of protein sources in the diet when assessing their impact on MASLD[74]. In conclusion, although HPD may confer certain benefits, it can also lead to negative outcomes in individuals with MASLD, particularly when consumed in excess or derived from less healthy sources. Therefore, a balanced and judicious approach to protein intake is crucial in managing and mitigating the risks associated with this metabolic condition.

Different kinds of proteins

The type of protein consumed appears to significantly influence the development and progression of MASLD. An international multidisciplinary expert consensus recommends that patients with MASLD should prioritize the consumption of healthy protein sources, primarily from plants while reducing the intake of red meat and processed meats[75]. This recommendation is corroborated by a case-control study that identified a significant association between plant protein intake and a reduced risk of MASLD, whereas increased meat protein intake was positively correlated with a higher risk[70]. Further evidence is provided by a comprehensive cross-sectional study conducted on the general adult population in the Netherlands in which Rietman et al[76] identified a negative correlation between plant protein intake and the characteristics of MASLD. Conversely, the intake of animal protein was positively associated with increased lipid accumulation in the liver, indicating that the dietary source of protein may differentially affect liver health.

In a separate cross-sectional study involving 505 participants aged 6 years to 18 years, a higher consumption of animal protein was significantly correlated with an increased likelihood of developing MASLD in pediatric and adolescent populations. In contrast, a greater intake of plant-based protein was significantly associated with a reduced risk of MASLD. Notably, this study did not find any significant association between total protein intake and the risk of MASLD, underscoring the importance of the type of protein consumed[77].

Furthermore, the intake of specific dietary amino acids, such as aromatic amino acids, BCAAs, and sulfur amino acids, has been shown to potentially exert a negative impact on the liver condition of individuals with MASLD, underscoring the importance of not only the type of protein but also the specific amino acid composition in the diet[78]. In conclusion, the evidence indicates that plant-based proteins may confer protective effects against MASLD, whereas animal proteins, particularly those derived from red and processed meats, may elevate the risk. Consequently, dietary modifications that prioritize plant-based protein sources and restrict the consumption of animal proteins, especially those rich in saturated fats, could be advantageous for the prevention and management of MASLD.

The preceding sections have thoroughly analyzed the association between diet and MASLD, demonstrating that both the quantity and source of protein intake are critical factors influencing this condition. Both excessive and insufficient protein consumption can potentially have detrimental effects on liver health. Furthermore, the source of protein is of significant importance as plant-based proteins generally appear to be more advantageous than animal proteins, especially those from red and processed meats[79]. The specific amino acid composition of proteins adds complexity to this issue with certain amino acids, such as BCAAs and glutamine, offering protective benefits for liver health, whereas elevated levels of others, such as homocysteine, can increase the risk of disease. Furthermore, the effects of various protein types differ across populations. For example, in individuals with obesity, low-protein diets have been shown to reduce hepatic lipid accumulation and liver damage. Conversely, in individuals with type 2 diabetes, HPD can significantly improve glycemic control and decrease liver fat accumulation.

These complex findings suggest that tailored dietary recommendations are warranted. For individuals at risk of or suffering from MASLD, HPD may be beneficial, particularly if the protein is primarily derived from plant sources. Plant-based proteins, such as those found in legumes, have been shown to exert favorable effects on liver health and overall metabolic regulation[80-82]. This recommendation is further substantiated by evidence indicating that plant-based proteins can reduce the risk of CKD, a condition frequently associated with MASLD. Research has demonstrated that substituting one serving of red meat with plant-based proteins like beans is linked to a 31.0%-62.4% reduction in the risk of developing CKD[83].

Additionally, MASLD is a complex condition influenced by a multitude of risk factors, including obesity, insulin resistance, gut microbial dysbiosis, and genetic predispositions[84,85]. Obesity, particularly characterized by visceral adiposity, constitutes a major risk factor for MASLD due to its association with various metabolic disturbances[86]. Insulin resistance plays a crucial role in the pathogenesis of MASLD; when the body fails to utilize insulin effectively, it results in elevated blood glucose levels, contributing to hepatic fat accumulation and inflammation[87]. The presence of type 2 diabetes mellitus further exacerbates the risk of MASLD as chronic hyperglycemia and related metabolic abnormalities inherent in diabetes promote the development of fatty liver[88]. Additionally, metabolic syndrome, which encompasses a constellation of conditions such as obesity, hypertension, insulin resistance, and dyslipidemia, markedly elevates the risk of MASLD[89,90]. Dyslipidemia, characterized by elevated TG, reduced high-density lipoprotein cholesterol, and increased small, dense low-density lipoprotein particles, is prevalent in MASLD and is associated with an increased risk of cardiovascular diseases, thereby contributing to liver fat deposition[91,92].

Sarcopenia, characterized by the loss of muscle mass and strength, constitutes an independent risk factor for MASLD. Notably, sarcopenic obesity is particularly associated with an elevated risk of MASLD compared with obesity alone[93,94]. Additionally, CKD is correlated with an increased risk of MASLD, potentially due to shared metabolic abnormalities and the influence of renal dysfunction on systemic metabolism[95]. Certain ethnic groups, such as South Asians, may exhibit a heightened predisposition to MASLD, attributable to genetic factors and lifestyle patterns[96]. Consequently, when evaluating dietary interventions for patients with MASLD, it is imperative to consider other coexisting medical conditions, advocating for personalized dietary regimens.

Personalized nutrition (PN) is transitioning from a conceptual framework to clinical application by integrating multilayered individual data to provide dietary recommendations that surpass generic guidelines[97,98]. For example, a recently conducted 12-week randomized controlled trial involving Chinese adults with overweight or obesity demonstrated that a PN intervention resulted in significantly greater reductions in body mass index, body fat percentage, waist circumference, and atherogenic lipids, mediated largely by improved diet quality and higher physical-activity levels[99].

Recent evidence highlighted the critical need for PN interventions in the management of MASLD. Vrentzos et al[100] argued that the efficacy of nutraceuticals was significantly influenced by host genetics, microbiome composition, and metabolic phenotype. Consequently, they advocated for the abandonment of “one-size-fits-all” approaches in favor of precision strategies. Technological advancements are enhancing the precision and applicability of these models. Innovations such as next-generation sequencing and point-of-care microfluidic genotyping facilitate the rapid and cost-effective identification of genetic variants pertinent to nutrient metabolism. Concurrently, artificial intelligence systems integrate these genetic variants with phenotypic and lifestyle data to generate personalized meal plans[101,102]. Clinical Nutritional Information Systems are being implemented in healthcare settings to standardize these processes, alleviate documentation burdens, and ensure real-time updates as patient parameters evolve.

Metabotyping approaches, which categorize individuals based on comprehensive profiles of metabolomics, microbiome, and habitual diet, enable the precise prevention of cardiometabolic diseases without necessarily revealing genetic risks[103,104]. Defining safe and effective protein quantities will require large, well-designed randomized controlled trials followed by meta-analyses that incorporate rigorous quality assessment. Future work should prioritize such randomized controlled trials, synthesize their findings through systematic reviews, and then integrate nutrigenomics, microbiome profiling, and real-time metabolomics to build adaptive algorithms capable of matching each patient with MASLD with the most effective nutraceutical combination and dietary pattern[105].

LIMITATIONS

While this review provided a consolidated map of the research on HPD and MASLD over the past 5 years, its scope and interpretation are subject to inherent constraints. First, due to differences among research in protein thresholds (1.2-2.0 g/kg/day), metabolic phenotypes, and MASLD diagnostics, quantitative pooling was precluded and our conclusions remain directional. We primarily discussed protein sources at a high level and lack the effects of specific foods on MASLD. Second, many mechanisms outlined herein rest on animal data and must be verified in humans, especially given the species-specific nuances of lipid metabolism, the gut microbiome, and the complexity of human diet. Third, some evidence supporting the importance of protein source are derived from observational studies, and these conclusions require validation through more randomized controlled trials to establish causality. Moreover, until multi-omics-driven, longitudinal trials define robust, clinically validated biomarkers and decision algorithms, personalized protein prescriptions for MASLD remain aspirational and need more randomized controlled trials and synthesis of their findings through systematic reviews.

CONCLUSION

The existing body of evidence presents a somewhat inconsistent narrative concerning the influence of protein intake on MASLD. Several studies have underscored the advantages of plant-based proteins, whereas other research suggests that excessive protein consumption, irrespective of its source, may have adverse effects. Consequently, it is imperative to ascertain an optimal level of protein intake that maximizes benefits while minimizing potential risks. Animal studies could be particularly instrumental in this context as they may clarify whether the deleterious effects of HPD are dose dependent.

Further research into the specific mechanisms by which various types of proteins and amino acids affect liver health is also necessary. This research could include examining the interactions between proteins and metabolic pathways as well as the potential involvement of gut microbiota in mediating these effects. For instance, plant protein shows promise against MASLD, and future work should pinpoint the bioactive peptides responsible. Given the variable impacts of protein intake across different populations, future research should also emphasize personalized dietary recommendations based on individual characteristics such as obesity status, presence of diabetes, and genetic predispositions. For example, the current definition of HPD remains ambiguous with wide variation in its thresholds. Future animal and clinical studies could incorporate a graded series of protein levels to clarify how dietary protein concentration influences MASLD risk. By addressing these research gaps, we can develop more effective and tailored dietary strategies for the prevention and management of MASLD.